Non Surface Active Agent Non Polymeric Agent Hydro-Alcoholic Foamable Compositions, Breakable Foams and Their Uses

ABSTRACT

A substantially surface active agent-free and substantially polymeric agent-free foamable composition which includes short-chain alcohol, water, fatty alcohol or fatty acid or a combination of fatty alcohol and fatty acid and propellant. A substantially surface active agent-free and substantially polymeric agent-free foamable composition which includes water, fatty alcohol or fatty acid and propellant. A method of treatment using a substantially surface active agent-free and substantially polymeric agent-free foamable composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims the benefit ofInternational Application No. PCT/IB10/02238, filed Jul. 29, 2010, whichclaims the benefit of U.S. Provisional Application No. 61/229,338 filedon Jul. 29, 2009, the contents of all of which are hereby incorporatedby reference in their entireties herein.

BACKGROUND

Foam compositions with high amounts of alcohol are known in the art.Alcohol-based compositions are useful because of the anti-microbialproperties of alcohol and the ability for alcohol to dissolve certainactive agents.

Foams and, in particular, single-phase foams are complicated systemswhich do not form under all circumstances. Slight shifts in foamcomposition, such as by the addition of active ingredients or theremoval of any of the essential ingredients, may destabilize the foam.

The prior art teaches hydro-alcoholic foam compositions requiresignificant amounts of short-chain alcohols (namely, ethanol, propanol,isopropanol, butanol, iso-butanol, t-butanol and pentanol), water, fattyalcohols, polymer and surfactant to form a foam. These compositionsrequire various surfactants, such as, non-ionic surfactants, anionic,cationic, zwitterionic, amphoteric and ampholytic surfactants, asessential components.

Surfactants are known as essential ingredients in foam compositionsbecause of their amphiphilic properties and because they are consideredessential in forming a foam. However, many surfactants are known to beirritating when left on the skin, as they can extract lipids from theskin, thereby damaging skin barrier and exposing the skin to contactwith pro-inflammatory factors. (See, Dermatitis, Vol. 33(4) 217-225, 11Apr. 2006, John Wiley & Sons).

Lower alcohols are defatting agents. They are known to extract skinfats, thereby disrupting skin barrier function and causing irritation.They are known to cause skin to become dry and cracked (See, forexample, Industrial Guide to Chemical and Drug Safety, by T. S. S.Dikshith, Prakash V. Diwan, John Wiley & Sons, Inc., 2003, p. 228-9).

Thus the combination of a short chain alcohol and a surfactant can havea doubly undesirable irritating and defatting effect, as well as thedrawback of enhanced delivery of drugs through the skin, which resultsin increased systemic exposure (which is undesirable for topicaltreatment of the skin).

Hydro-alcoholic foams, as described in the prior art are inherentlythermally unstable, and they will collapse upon exposure to the skin andbody (at temperatures around 37° C.). They are therefore commonly termed“quick breaking” foams. Typically, when a quick breaking foam is appliedto fingers (as is usually done in order to apply a drug to a targetarea), it melts and rapidly (on exposure to body temperature of about37° C.) and collapses leaving behind a small pool of liquid. The thermalinstability of the foam makes it difficult to apply to a large targetarea by first administering the foam to the hands and then spreading thefoam onto the affected area.

SUMMARY

The present application relates to foamable formulations and foams andtheir uses comprising, short chain alcohols (“SCA's”), and especiallyethanol. In one or more embodiments the short chain alcohol isisopropanol. In one or more embodiments the SCA's are needed as part ofa drug carrier. For example certain drugs require alcohol in order tosolubilize them. In one or more other embodiments, the SCA's areprovided to facilitate or enhance the transdermal penetration ordelivery of a drug. In one or more additional cases, the SCA's areprovided to have a defatting effect at the target site, for examplewhere the site of treatment is oily and the defatting effect of alcoholis desirable.

Unexpectedly, it has been discovered that quality hydro-alcoholicfoamable formulations and foams can be achieved which upon dispensingare thermally stable, for example, for at least 60 seconds at 36° C.,yet easily breakable upon application of shear force, without thepresence of significant amounts of standard surface active agents knownin the art. In other words contrary to the prior art these foams do notcollapse rapidly on exposure to body temperature but remain stable for asufficient period of time so that they can be conveniently applied to atarget site without having to take special precautions, such as onlyapplying the foam to a cold surface. Also, surprisingly they can formquality foamable formulations and foams even in the absence of customarypolymeric agents. Thus, in one or more embodiments, there is provided asubstantially surfactant free hydro-alcoholic foamable formulation orfoam. In one or more preferred embodiments the hydro-alcoholicformulations and foams are free of surface active agents. Thus, in oneor more embodiments, there is also provided a substantially polymericagent free hydro-alcoholic foamable formulation or foam. In one or morepreferred embodiments the hydro-alcoholic formulations and foams arefree of surfactants and polymeric agents. Moreover, it has been furtherdiscovered that these formulations and foams can be achieved over alarge range of alcohol content. Thus, for certain delivery systems thereis provided a surfactant-free foamable and or polymeric agent freecomposition and foam, comprising about a medium level to about a veryhigh level of content of a short-chain alcohol.

In one or more embodiments there is provided a safe and effectivefoamable carrier composition and foam comprising a short chain alcohol(“SCA”), water, a foaming booster and a liquefied or compressed gaspropellant at a concentration of about 3% to about 30% by weight of thetotal composition, wherein the percent by weight is based on weightfoamable composition; wherein the ratio of composition other thanpropellant to propellant is from about 100:3 to about 100:30. In one ormore other embodiments there is provided a safe and effective foamablepharmaceutical or cosmetic composition and foam comprising an effectiveamount of a pharmaceutical or cosmetic agent, a short chain alcohol(“SCA”), water, a foaming booster and a liquefied or compressed gaspropellant at a concentration of about 3% to about 30% by weight of thetotal composition wherein the percent by weight is based on weightfoamable composition; wherein the ratio of composition other thanpropellant to propellant is from about 100:3 to about 100:30. Thefoaming booster surprisingly does not need to include a surfactant; andcan include at least one fatty alcohol or one or at least one fatty acidor a combination thereof or a synergistic combination of two or morefatty alcohols. The SCA is present in a substantial amount. By asubstantial amount is meant that the alcohol is present at a %concentration by weight at which it is capable of having a defoamingeffect and/or an irritating effect. In one or more embodiments thealcohol is at least about 15% by weight. In other embodiments it is atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, or at least about 60% by weight. In one or moreembodiments the SCA is at a concentration between about 15% to about 65%by weight, or about 20% to about 60% by weight, preferably between about25% to about 55% by weight, and more preferably between about 30% toabout 50% by weight. The carrier and pharmaceutical composition issubstantially surfactant free and preferably does not contain asurfactant.

In one or more embodiments there is provided a substantially surfactantfree and polymeric agent free foamable composition comprising a shortchain alcohol, water, a foaming booster comprising at least one fattyalcohol or at least one fatty acid or a combination thereof andliquefied or compressed gas propellant at a concentration of about 3% toabout 30% by weight of the total composition. The percent by weight isbased on weight foamable composition; wherein the ratio range ofcomposition other than propellant to propellant is from about 100:3 toabout 100:30; and wherein upon dispensing the foamable carriercomposition forms a foam of quality that is thermally stable at atemperature of 36° C. having a collapse time of about or more than 60seconds.

In one or more embodiments there is provided a substantially surfactantand polymeric agent free foamable composition comprising a short chainalcohol, water, a foaming booster comprising at least one fatty alcoholor at least one fatty acid or a combination thereof or a synergisticcombination of two or more fatty alcohols and a liquefied or compressedgas propellant at a concentration of about 3% to about 30% by weight ofthe total composition; wherein the percent by weight is based on weightfoamable composition; wherein the ratio range of composition other thanpropellant to propellant is from about 100:3 to about 100:30. In one ormore embodiments the ratio between a first fatty alcohol and a secondfatty alcohol is between about 11:5 and about 5:11.

In one or more embodiments there is provided a method of preventing orameliorating or eliminating or treating or alleviating a dermatologicalor mucosal disorder, comprising: applying a substantially surfactant andpolymeric free foamable composition to a surface having a dermatologicalor mucosal disorder in need of treatment, said composition comprising ashort chain alcohol, water, a foaming booster comprising at least onefatty alcohol or at least one fatty acid or combination thereof or asynergistic combination of two or more fatty alcohols and a liquefied orcompressed gas propellant at a concentration of about 3% to about 30% byweight of the total composition; wherein the percent by weight is basedon weight foamable composition; wherein the ratio range of compositionother than propellant to propellant is from about 100:3 to about 100:30;and wherein upon dispensing the foamable carrier composition forms afoam that is thermally stable at a temperature of 36° C. having acollapse time of about or more than 60 seconds.

Unexpectedly, it has been further discovered that quality hydro foamableformulations and foams, which are substantially free of SCA, can beachieved without the presence of significant amounts of standard surfaceactive agents known in the art, by using the carrier discovered forhydro-alcoholic foams without the SCA. Also surprisingly they can formquality foamable formulations and foams even in the absence of customarypolymeric agents. Thus, in one or more embodiments, there is provided asubstantially surfactant free hydro foamable formulation or foam. In oneor more preferred embodiments the hydro formulations and foams are freeof surface active agents. Thus, in one or more embodiments, there isalso provided a substantially polymeric agent free hydro foamableformulation or foam. In one or more preferred embodiments the hydroformulations and foams are free of polymeric agents. Thus, in one ormore embodiments, there is provided a substantially surfactant free andpolymeric agent free hydro-foamable formulation or foam. Thus, in one ormore other embodiments, there is provided a surfactant free andpolymeric agent free hydro-foamable formulation or foam.

In one or more embodiments, the foamable formulation is clear ortransparent when pressurized by the propellant. In a further embodimentthe foamable formulation is clear or transparent prior to addition ofone or more active agents at which point it forms a homogenoussuspension of active agent. Yet, in certain other embodiments theformulation is a suspension prior to addition of propellant and remainsa suspension when pressurized by the propellant.

According to an embodiment the one or more active agents is selectedfrom the group consisting of an active herbal extract, an acaricides, anage spot and keratose removing agent, an allergen, an alpha hydroxylacid, an analgesic agent, an anesthetic, an immunogenic substance, anantiacne agent, an antiallergic agent, an antiaging agent, anantibacterial agent, an antibiotic, an antiburn agent, an anticanceragent, an antidandruff agent, an antidepressant, an antidermatitisagent, an antiedemic anent, an antifungal agent, an antihistamine, anantihelminth agent, an antihyperkeratolyte agent, an anti-infectiveagent, an antiinflammatory agent, an antiirritant, an antilipemic agent,an antimicrobial agent, an antimycotic agent, an antioxidant, anantiparasitic agent, an anti-pigmentation agent, an antiproliferativeagent, an antipruritic agent, an antipsoriatic agent, an antirosaceaagent, an antiseborrheic agent, an antiseptic agent, an antiswellingagent, an antiviral agent, an anti-wart agent, an anti-wrinkle agent, anantiyeast agents, an astringent, a beta-hydroxy acid, benzoyl peroxide,benzoyl chloride a, topical cardiovascular agent, a chemotherapeuticagent, a corticosteroid, an immunogenic substance, a dicarboxylic acid,a disinfectant, a fungicide, a hair growth regulator, a haptene, ahormone, a hydroxy acid, an immunosuppressant, an immunoregulatingagent, an immunomodulator, an insecticide, an insect repellent, akeratolytic agent, a lactam, a local anesthetic agent, a lubricatingagent, a masking agent, a metals, a metal oxide, a mitocide, aneuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a protein, a photodynamic therapyagent, a radical scavenger, a refatting agent, a retinoid, a sanative, ascabicide, a self tanning agent, silicone talc, a skin protective agent,a skin whitening agent, a steroid, a steroid hormone, a steroidalantiinflammatory agent, a vasoconstrictor, a vasodilator, a vitamin, avitamin A, a vitamin A derivative, a vitamin B, a vitamin B derivative,a vitamin C, a vitamin C derivative, a vitamin D, a vitamin Dderivative, a vitamin D analog, a vitamin F, a vitamin F derivative, avitamin K, a vitamin K derivative, a wound healing agent and a wartremover and mixtures thereof. In a further embodiment the active agentis selected from the group consisting of mometasone furoate orbetamethasone valerate, diclofenac sodium, and metronidazole

In an embodiment the composition comprises a fatty alcohol. The fattyalcohol can be a straight chain fatty alcohol, a saturated fattyalcohol, an unsaturated fatty alcohol, a hydroxyl substituted fattyalcohol or a branched fatty alcohol. In an embodiment the fatty alcoholis a therapeutically active fatty alcohol.

In additional embodiments, the foamable composition comprises a fattyacid. The fatty acid can be a straight chain fatty acid, a saturatedfatty acid, an unsaturated fatty acid, a hydroxyl fatty acid or abranched fatty acid. In an embodiment the fatty acid is atherapeutically active fatty acid. According to additional embodimentsthere is provided a method of producing a foamable composition,including:

-   1. providing a foamable therapeutic composition including a    therapeutic agent at a therapeutically effective concentration, a    short chain alcohol, for example, at a concentration of about 20% to    about 60% by weight, a hydroalcoholic composition foaming booster    (including at least a fatty alcohol or a fatty acid) and water-   2. introducing the foamable composition in an aerosol packaging    assembly, comprising a container, suitable for containing a    pressurized product and a valve, capable of extruding a foam; and-   3. introducing to the aerosol packaging assembly a liquefied or    compressed gas propellant at a concentration of about 3% to about    30% by weight of the total composition.

In one or more certain embodiments the SCA content can be in excess of60%, or in excess of 65%, however, as the level reaches towards 70% itis harder to prepare a satisfactory formulation and higher levels ofhydro-alcoholic foam booster can be appropriate. In certaincircumstances having both fatty acid and fatty alcohol may help. Thegreater challenge to form hydro-alcoholic foamable formulations and foamwith very high levels of SCA's is presumably without being bound by anytheory because of the defoaming and themolabile properties of thealcohol, the high level of alcohol and the lower level of water.

According to further embodiments there is provided a method ofpreventing, treating ameliorating or eliminating a disorder by selectingand releasing on to a convenient surface a safe and effectivepharmaceutical or cosmetic foamable composition comprising an effectiveamount of a pharmaceutical or cosmetic agent, a short chain alcohol(“SCA”), water, a foaming booster and a liquefied or compressed gaspropellant at a concentration of about 3% to about 30% by weight of thetotal composition; directing the released foam on to a target on apatient in need; applying a shear force to and spreading the foam overthe target surface such that after a simple rub the foam is no longervisible to the naked eye as it is absorbed rapidly on to the targetsurface.

According to one of more further embodiments the disorder treated by thefoamable composition is selected from the group consisting of adermatose, a dermatitis, a vaginal disorder, a vulvar disorder, an analdisorder, a disorder of a body cavity, an ear disorder, a disorder ofthe nose, a disorder of the respiratory system, a bacterial infection, afungal infection, a viral infection, dermatosis, dermatitis, parasiticinfections, disorders of hair follicles and sebaceous glands, scalingpapular diseases, benign tumors, malignant tumors, reactions tosunlight, bullous diseases, pigmentation disorders, disorders ofcornification, pressure sores, disorders of sweating, inflammatoryreactions, xerosis, ichthyosis, an allergy, a burn, a wound, a cut, achlamydia infection, a gonorrhea infection, hepatitis B, herpes,HIV/AIDS, human papillomavirus (HPV), genital warts, bacterialvaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranlomavenereum, mucopurulent cervicitis (MPC), molluscum contagiosum,nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders,vulvodynia, vulvar pain, a yeast infection, vulvar dystrophy, vulvarintraepithelial neoplasia (VIN), contact dermatitis, osteoarthritis,joint pain, an hormonal disorder, a pelvic inflammation, endometritis,salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer ofthe vulva, cancer of the vagina, vaginal dryness, dyspareunia, an analand rectal disease, an anal abscess/fistula, anal cancer, an analfissure, an anal wart, Crohn's disease, hemorrhoids, anal itch, pruritusani, fecal incontinence, constipation, polyps of the colon and rectum.

According to further embodiments there is provided the use of a foamablecomposition in the manufacture of a medicament for preventing ortreating a dermatological or a mucosal disorder, the foamablecomposition comprising: a short chain alcohol; water; a foaming boostercomprising at least one fatty alcohol or at least one fatty acid or acombination thereof; and a liquefied or compressed gas propellant at aconcentration of about 3% to about 30% by weight of the totalcomposition; wherein the foamable composition is substantiallysurfactant free; wherein the foamable composition is substantiallypolymeric agent free; wherein the percent by weight is based on weightfoamable composition; wherein the ratio range of composition other thanpropellant to propellant is from about 100:3 to about 100:30; andwherein upon dispensing the foamable composition forms a foam of qualitythat is thermally stable at a temperature of 36° C. having a collapsetime about or more than 60 seconds. In some embodiments, the foamablecomposition of the use further includes at least one active agent. Inother embodiments, the foamable composition of the use comprises 0% to0.4% surfactant and 0% to 0.2% polymeric agent.

DETAILED DESCRIPTION Foamable Composition and Foam Properties

The ability to achieve quality foam with a substantial concentration ofat least one short chain alcohol without a surfactant is surprising,because such alcohols are not prone to creating a foam. The challenge isnot just to achieve a quality foam but also to attain a formulation thatwill satisfy a plurality of two, three, four, five, six or more of thefollowing property specifications simultaneously.

-   1. Uniformity: The composition should be formulated so that it is    and can remain uniform without phase separation or precipitation    over time. This property is of high importance when the product is    intended to be a pharmaceutical product. In some embodiments the    formulation is shaken before use and is readily re-homogenized upon    shaking so the composition is uniform when dispensed.-   2. Flowability: The composition, when placed in an aerosol container    and pressurized should be flowable such that it can be expelled    through the canister valve. It should preferably also be shakable    inside the container. These requirements create a formulation    challenge, because low or non-viscous flowable and shakable    compositions are prone to undergo phase separation or precipitation.-   3. Quality: Upon release from the can, the composition should    generate a foam of good or excellent quality having low density and    small bubble size.-   4. Stability/Breakability: The fine balance between stability and    breakability of the foam coming out of the container is very    delicate: on one hand the foam should preferable not be “quick    breaking”, i.e., it should be at least short term stable upon    release from the pressurized container and not break as a result of    exposure to skin temperature; and on the other hand, it should be    “breakable”, i.e., it should spread easily, break down and absorb    into the skin or membrane upon application of mild shear force.-   5. Skin Feeling: To ensure patient compliance the skin feeling after    application should be pleasant, and greasy or waxy residues should    be minimal-   6. Non-irritating: The above requirements should be achieved with    the awareness that formulation excipients, especially surfactants,    can be irritating, and should preferably be eliminated from the    composition or reduced as much as possible.-   7. Delivery: Finally, the composition should also be designed to    ensure efficient delivery of a therapeutic agent into the target    site of treatment.

Based on extensive investigations and trial and error experiments, ithas been found that such properties can be achieved for formulations asdescribed below.

Compositions

All % values are provided on a weight (w/w) basis.

In one or more embodiments there is provided a foamable compositionincluding:

-   1. a short chain alcohol-   2. a foaming booster, at least one fatty alcohol, or at least one    fatty acid, or a combination thereof or a synergistic combination of    two or more fatty alcohols; and-   3. water; and-   4. a liquefied or compressed gas propellant.

In one or more other embodiments the fatty acid(s) and fatty alcohol(s)may combine to have a synergistic effect. In one or more furtherembodiments the fatty acid(s) and fatty acids(s) may combine to have asynergistic effect. In one or more embodiments the synergism is toimprove foam quality. In one or more other embodiments the synergism isto improve foam thermal stability. In one or more other embodiments thesynergism is to improve foam collapse time, which is can be an indicatorof thermal stability.

In one or more embodiments the foamable composition is substantiallysurfactant free. In one or more other embodiments it is essentiallysurfactant free, namely a non surfactant composition.

In one or more embodiments the foaming booster combination is asynergistic combination that can improve the foam quality and or thermalstability of the composition.

In one or more embodiments the short chain alcohol, is preferablyethanol. In one or more embodiments the short chain alcohol, ispreferably isopropanol. In one or more embodiments the short chainalcohol is at least about 15% by weight of the composition. In one ormore embodiments the short chain alcohol is at a concentration of about20% to about 60% by weight. In one or more embodiments the short chainalcohol is at a concentration of about 30% to about 60% by weight. Inone or more embodiments the short chain alcohol is at a concentration ofabout 40% to about 60% by weight. In one or more other embodiments theSCA is propanol or butanol or a branched chain derivative thereof suchas isopropanol or iso-butanol. In one or more embodiments it is apentanol.

Upon release from an aerosol container, the foamable composition formsan expanded breakable foam suitable for topical administration. In oneor more other embodiments the foam is a breakable foam that is thermallystable upon dispensing yet breaks easily upon application of shearforce.

The foamable composition is suitable for administration to the tovarious body areas, including, but not limited to the skin, a bodysurface, a body cavity, a mucosal surface, e.g., the mucosa of the nose,mouth and eye, the ear, the respiratory system, the vagina or the rectum(severally and interchangeably termed herein “target site”)

According to one or more embodiments, the foamable composition furthercomprises a cosmetic or a pharmaceutical active agent (severally andinterchangeably termed herein “active agent”).

In one or more embodiments there is provided a foamable compositionincluding:

-   1. an active agent at an effective concentration;-   2. a short chain alcohol, preferably ethanol, at a concentration of    about 20% to about 60% by weight;-   3. about 0.1% to about 10% by weight of at least one fatty alcohol,    or at least one fatty acid, or a synergistic combination of two or    more fatty alcohols;-   4. water; and-   5. a liquefied or compressed gas propellant.

In one or more embodiments the composition is substantially polymericagent free. In one or more embodiments the polymeric agent comprisesless than about 0.2% by weight; less than about 0.1% by weight; or lessthan about 0.05% by weight of the formulation. In one or moreembodiments the composition is essentially polymeric agent freecomprising less than about 0.01% by weight of the formulation or havingno polymer.

In one or more embodiments, at least a portion of the therapeutic agentis suspended or dissolved evenly throughout the entire composition.

In one or more embodiments, the foam composition is clear andtransparent when placed under the pressure of the propellant. In one ormore embodiments, the composition is transparent upon pressurization bythe gas propellant.

It was found that formulations containing high amount of a SCA (such asethanol) are not prone to foaming when using combinations of differenttypes of surfactants and different types of polymers. Foams producedwere not of quality and or collapsed rapidly. It was found that thecombination of at least two suitable fatty alcohols (e.g stearyl alcoholwith cetyl alcohol or cetyl alcohol with myristyl alcohol) or acombination of at least one fatty alcohol with at least one fatty acid(e.g stearyl alcohol with stearic acid) or the combination of at leasttwo suitable fatty acids (e.g myristic acid with stearic acid) producedgood to excellent quality short term stable foams in the absence ofcustomary surfactants and or in the absence of customary polymericagents. It was further discovered that fatty alcohols or fatty acidswith a saturated carbon chain of between 14 to 18 or between 16 to 18carbons have outstanding foam boosting properties. Furthermore, theformulations of the present invention can provide foams of quality inthe presence of various active ingredients.

Surprisingly, it was discovered that that the combination of at leasttwo suitable fatty alcohols have synergistic foam boosting properties inthe absence of customary surfactants and or in the absence of customarypolymeric agents. For example when cetyl alcohol or myristyl alcoholwere used alone in hydro-alcoholic formulations, poor and fairly goodfoams were obtained respectively. Surprisingly however, when myristylalcohol was combined with cetyl alcohol at a 1:1 ratio, a short termstable breakable foam of excellent quality was obtained. Thus, thecombination of cetyl and myristyl alcohol has a synergistic foamboosting effect.

It was further found that when cetyl alcohol or stearyl alcohol wereused alone in hydro-alcoholic formulations, fairly good and good foamswere achieved respectively. Surprisingly however, when stearyl alcoholwas combined with cetyl alcohol at a 1:1 ratio, a short term stablebreakable foam of excellent quality was obtained. Thus, the combinationof cetyl and stearyl alcohol has a synergistic foam boosting effect.

Furthermore, when stearyl alcohol and stearic acid were used alone inhydro-alcoholic formulations, good quality foams were obtained.Surprisingly, breakable foam of excellent quality, having a low densitywas also obtained with a combination of stearic acid with stearylalcohol at a 1:1 ratio.

Thus in one or more embodiments there is provided a hydro-alcoholicfoamable formulation which provides an excellent breakable foam. In oneor more embodiments the foam displays a collapse time of about 60 sec ormore, or of about 90 seconds or more, or of about 120 seconds or more,or of about 150 seconds or more, or of about 180 seconds or more at 36°C. In other words it displays a thermal stability on exposure to a bodysurface at normal body temperature.

In one or more embodiments the foam displays a collapse time of about 60seconds or less, or of about 50 seconds or more, or of about 40 secondsor less, or of about 30 seconds or less at 36° C. In other words itdisplays a thermal liability on exposure to a body surface at normalbody temperature.

In one or more embodiments the fatty acid or fatty alcohol has 14 to 18carbon atoms in its carbon chain. In one or more embodiments the fattyacid or fatty alcohol has 16 to 18 carbon atoms in its carbon chain. Inone or more embodiments the fatty acid or fatty alcohol has 18 carbonatoms in its carbon chain. In one or more other embodiments the fattyalcohol or fatty acid has 14 to 22 carbon atoms in its carbon chain. Inone or more further embodiments the fatty alcohol or fatty acid has 16to 22 carbon atoms in its carbon chain.

In one or more embodiments there is provided a foaming boostercomprising at least one fatty alcohol or at least one fatty acid or acombination thereof. In one or more embodiments the combination is asynergistic combination. In certain embodiments the synergism results inan improved foam quality. In certain embodiments the synergism resultsin a thermal stability or in an improved thermal stability. In certainembodiments the thermal stability is exhibited when the composition isplaced on a mammal at normal body temperature. In an embodiment themammal is a human.

In one or more other embodiments the foaming booster consistsessentially of at least one fatty alcohol or at least one fatty acid ora combination thereof. In one or more other embodiments the foamingbooster consists essentially of at least two fatty alcohols. In one ormore other embodiments the foaming booster consists essentially of atleast two fatty acids. In one or more other embodiments the foamingbooster is between about 1% and about 10% by weight of the composition.

In one or more embodiments the foamable formulation comprises asynergistic combination of two or more fatty alcohols to achieve a foamwith thermal stability. In one or more embodiments, the foamableformulation comprises a synergistic combination of two or more fattyacids to achieve a foam with thermal stability. In one or moreembodiments the foamable formulation comprises a synergistic combinationof at least one fatty acid and at least one fatty alcohol to achieve afoam with thermal stability. In one or more embodiments, the foamableformulation comprises a synergistic combination of two or more fattyalcohols or fatty acids or a fatty acid and fatty alcohol at a ratio ofabout 1:1. By about it is intended to provide for a variation of 35% orof 30% or of 25% or of 20% or of 10% or of 5% or of 1% or any % betweenany of these amounts. If there are more than two fatty alcohols then inone or more embodiments the ratio between a first fatty alcohol (havingthe highest concentration) and the remaining fatty alcohols is betweenabout 2:1 and about 1:2, or if there are more than two fatty acids thenin one or more embodiments the ratio between the first fatty acid(having the highest concentration) and the remaining fatty acids isbetween about 2:1 and about 1:2, or if there is a combination of fattyacids and fatty alcohols and there are more than one of one or both oftypes in one or more embodiments the ratio between the total fattyalcohols and the total fatty acids is between about 2:1 and about 1:2.In one or more further embodiments the aforesaid ratios are betweenabout 11:5 and about 5:11, or are in certain embodiments are about 1:1.

Surprisingly, foam quality and properties can be strongly influenced bythe ratio of mixtures of two or more fatty alcohols, such as cetyl andstearyl alcohol or by the ratio of mixtures of two or more fatty acids,such as myristic acid and stearic acid or by the ratio of mixtures of atleast one fatty alcohol and at least one fatty acid, such a stearylalcohol and stearic acid.

Formulations having a cetyl:stearyl alcohol ratio of about 1:1generated, for example, a breakable foam of quality being thermallystable on being applied to a surface at 36° C. for at least 3 minutes.Whereas when the ratio of cetyl:stearyl alcohol was about more than11:5, or was about less than 5:11 no foam of quality was produced. Thus,in one or more embodiments, there is provided a hydro-alcoholic foamableformulation of good quality being thermally stable on being applied to asurface at 36° C. for at least a minute comprising about 1:1cetyl:stearyl alcohol. In one or more embodiments it is thermally stablefor at least two minutes. In one or more embodiments, it is thermallystable for at least three minutes. In one or more embodiments a quicklybreaking foam of fairly good quality was produced when the ratio wasabout 5:11 cetyl:stearyl alcohol.

Interestingly, when surfactant was removed from prior art formulations(Example 1 of U.S. Pat. No. 6,126,920) no foam was produced. Therefore,it appears that they rely on the surfactant present in combination withthe alcohol in the composition to produce quick-breaking foams incomplete contrast an teaching away from the surfactant-freehydro-alcoholic breakable foams, which are thermo stable at 36° C.established herein.

In one or more other embodiments the fatty alcohol synergisticcombination is cetyl and myristyl alcohol. In one or more otherembodiments the fatty alcohol synergistic combination is stearyl andmyristyl alcohol. In one or more other embodiments the fatty alcoholsynergistic combination is stearyl and cetyl alcohol. In one or moreembodiments, the ratio of fatty alcohols can be optimized in order toobtain foams of good or excellent quality. In an embodiment the ratiobetween at least two fatty alcohols is about 1:1. In an embodiment theratio between at least of two fatty alcohols is about between 11:5 and5:11. If there is more than two then in certain embodiments the ratiobetween the first (having the highest concentration) and the remainingfatty alcohols is between about 2:1 and about 1:2 or between about 11:5and about 5:11 or about 1:1.

Surprisingly, it was found that foam of quality can be influenced by theratio of combinations of at least two fatty acids (e.g myristic andstearic acid). Formulations having a myristic:stearic acid ratio ofabout 5:11 gave foams of good quality. In one or more embodiments, theratio of fatty acids can be optimized in order to obtain foams of goodor excellent quality.

Similarly, it has been found that foams containing cetostearyl alcoholin the composition have excellent quality and thermal stability at 36°C. It has further been found that foams with higher amounts ofcetostearyl alcohol have a lower density than foams containing loweramounts of cetostearyl alcohol. Thus, in one or more embodiments, thereis provided a hydro-alcoholic foamable formulation or foam comprisingbetween about 1% by weight and about 10% by weight of cetostearylalcohol. In other embodiments the range of cetostearyl alcohol isbetween about 0.1% by weight and about 10% by weight; about 1% by weightand about 15% by weight; about 2% by weight and about 10% by weight;about 3% by weight and about 10% by weight; about 4% by weight and about10% by weight; about 5% by weight and about 10% by weight; about 6% byweight and about 10%; about 7% by weight and about 10% by weight; about8% by weight and about 10% by weight; about 5% by weight and about 12%by weight; about 5% by weight and about 15% by weight; about 0.1% byweight and about 15% by weight; or about 0.1% by weight and about 5% byweight. In other embodiments the foam density is inversely correlated tothe concentration of cetostearyl alcohol in the formulation within therange of about 1% by weight and about 7.5% by weight. The above rangesin one or more embodiments apply to the total % by weight of fattyacids, or to the total % by weight of fatty alcohols or to the total %by weight of fatty acids and fatty alcohols.

Surprisingly it has been found that foamable formulations containingdifferent hydrocarbon propellants, produce breakable foams of good toexcellent quality and having a low density and thermally stability yetbreakable upon shear force. It was further found that the density ispositively correlated with the concentration of the propellant i.e thelower the propellant the lower the foam density. It was further foundthat foams of good quality obtained in hydro-alcoholic formulationscontaining a hydrocarbon propellant at a concentration up to about 30%.These foams were thermally stable at 36° C. for more than three minutesyet breakable upon shear force and had a low density. However, when theconcentration of propellant was increased to about 37%, only poorquality foams were produced.

In one or more embodiments, there is provided a foamable formulation orbreakable foam of good to excellent quality containing hydrocarbonpropellant having a low density and being thermally stable for more thanone, or two or three minutes at 36° C. yet breakable upon shear force.In one or more embodiments, there is provided a foam or a foamableformulation which comprises a hydrocarbon propellant selected from thegroup consisting of A-46 or Dymel 134a or AP-70. In one or moreembodiments, there is provided a foam having a low density generatedfrom a foamable formulation comprising at least one hydrocarbonpropellant. In one or more embodiments, there is provided a foam havinga density of less than about 0.2 g/ml; less than about 0.15 g/ml; lessthan about 0.1 g/ml; less than about 0.09 g/ml; less than about 0.08g/ml; less than about 0.07 g/ml; or less than about 0.06 g/ml generatedfrom a foamable formulation comprising a hydrocarbon propellant. In oneor more embodiments, hydro-alcoholic foams generated by hydrocarbonpropellants at concentrations lower than 30% w/w have a density betweenabout 0.06 g/ml and about 0.15 g/ml; or between about 0.03 g/ml andabout 0.2 g/ml. In one or more embodiments the density is positivelycorrelated with the concentration of the propellant. In one or moreembodiments the propellant concentration is within a range of about 6%by weight to about 14%; about 6% by weight to about 12%;about 6% byweight to about 10%; about 5% by weight to about 14%; about 6% by weightto about 16%; about 6% by weight to about 20%; about 6% by weight toabout 30% by weight about 20% by weight to about 30%; about 20% byweight to about 35%; or about 30% by weight to about 35% by weight.

In one or more embodiments, there is provided a foamable formulation orbreakable foam of good quality containing having a low density and beingthermally stable for more than one, or two or three minutes at 36° C.yet breakable upon shear force comprising isopropanol.

Short Chain Alcohol

A short chain alcohol according to one or more certain otherembodiments, has up to 6 carbon atoms in their carbon chain skeleton andone hydroxy group. Such short chain alcohols can be selected fromethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol,pentanol and isomers thereof (herein after “a pentanol) and hexanol andisomers thereof (herein after “a hexanol). In a preferred embodiment theshort chain alcohol is ethanol. The SCA is present in a substantialamount. By a substantial amount is meant that the alcohol is present ata % concentration by weight at which it is capable of having a defoamingeffect and or an irritating effect. In various embodiments the amount ofshort chain alcohol is above about 10%. In one or more embodiments thealcohol is at least about15% by weight. In other embodiments it is atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, or at least about 60% by weight. In one or moreembodiments the SCA is at a concentration between about 15% to about 65%by weight, or about 20% to about 60% by weight, preferably between about25% to about 55% by weight, and more preferably between about 30% toabout 50% by weight.

Fatty Alcohol

The hydro-alcoholic foamable composition foaming booster may include afatty alcohol. The fatty alcohol which acts as a foam adjuvant isincluded in the foamable compositions as a main constituent, to evolvethe foaming property of the composition and/or to stabilize the foam. Inone or more embodiments, the fatty alcohol is selected from the groupconsisting of fatty alcohols having 15 or more carbons in their carbonchain, such as cetyl alcohol and stearyl alcohol (or mixtures thereof).Other examples of fatty alcohols are myristyl alcohol (C14), arachidylalcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as well asalcohols with longer carbon chains (up to C50). In one or more preferredembodiments , the fatty alcohol is cetyl alcohol, stearyl alcohol,behenyl alcohol or myristyl alcohol and combinations thereof.

Fatty alcohols, derived from beeswax and including a mixture ofalcohols, a majority of which has at least 20 carbon atoms in theircarbon chain, are suitable as fatty alcohols in the context herein. Incertain embodiments the amount of the fatty alcohol required to supportthe foam system can be approximately inversely related to the length ofits carbon chains. Fatty alcohols are also useful in facilitatingimproved spreadability and absorption of the composition.

Fatty alcohols are amphiphatic, however unlike customary surfactants,they cannot usually function as stand-alone surfactants, because oftheir very weak emulsifying capacity. They are occasionally used asnon-ionic co-emulsifiers, i.e., and are commonly used as thickeners(Surfactants in personal care products and decorative cosmetics, byLinda D. Rhein, Mitchell Schlossman, Anthony O'Lenick, P., ThirdEdition, 2006, p. 247). Fatty alcohols are generally regarded as safeand they are not considered as irritants.

An important property of the fatty alcohols used in context of thecomposition disclosed herein is related to their therapeutic propertiesper se. Long chain saturated and mono unsaturated fatty alcohols, e.g.,stearyl alcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol(docosanol) have been reported to possess antiviral, antiinfective,antiproliferative and anti-inflammatory properties (see, U.S. Pat. No.4,874,794). Longer chain fatty alcohols, e.g., tetracosanol,hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are alsoknown for their metabolism modifying properties and tissue energizingproperties.

The concentration of a fatty alcohol or a combination of different fattyalcohols in the composition can in one or more embodiments range betweenabout 0.1% and about 10%, or between about 1% to about 15%. In certainembodiments, the concentration of the fatty acid can be selected fromthe group consisting of (i) between about 0.1% and about 1%, (ii)between about 1% and about 5%, and (iii) between about 5% and about 10%.In one or more embodiments, the fatty alcohol is at a concentration atabout 1% to about 3% by weight.

Fatty Acid

The hydro-alcoholic foamable composition foaming booster may include afatty acid or a combination of different fatty acids. In one or moreembodiments the fatty acid can have 16 or more carbons in its carbonchain, such as myristic acid (C14), hexadecanoic acid (C16) stearic acid(C18), arachidic acid (C20), behenic acid (C22), octacosanoic acid(C28), as well as fatty acids with longer carbon chains (up to C50), ormixtures thereof.

Optionally, the carbon atom chain of the fatty acid may have at leastone double bond; alternatively, the fatty acid can be a branched fattyacid. The carbon chain of the fatty acid also can be substituted with ahydroxyl group, such as 12-hydroxy stearic acid. In one or morepreferred embodiments, the fatty acid is hexadecanoic acid, stearic acidor behenic acid or myristic acid, or combinations thereof.

The fatty acid or combination of fatty acids according to one or moreembodiments can be included in the foamable composition in aconcentration of 0.1% to 5%. In one or more embodiments theconcentration of the combination of fatty acids in the composition canbe selected from the group consisting of (i) between about 0.1% byweight and about 1%, (ii) between about 1% by weight and about 5%, and(iii) between about 5% by weight and about 10%. In one or moreembodiments the a combination of myristylic acid and stearic acid isprovided.

Fatty Acid Combined with Fatty Alcohol

In one or more embodiments, the hydro-alcoholic foamable compositionfoaming booster may include a combination at least one fatty acid withat least one fatty alcohol to provide a thermally stable breakable foam.In one or more embodiments a thermally stable breakable foam ofexcellent quality is obtained by combining stearyl alcohol with stearicacid.

Propellant

The composition requires the addition of a propellant in order togenerate a foam.

Suitable propellants include volatile hydrocarbons such as butane,propane, isobutene or mixtures thereof. In one or more embodiments ahydrocarbon mixture AP-70 is used. In one or more other embodiments alower pressure hydrocarbon mixture AP-46 is used. Both contain butane,propane, isobutene although in different proportions. AP-46 is composedof about 16% w/w of propane, about 82% w/w of isobutane and about 2% w/wof propane. AP-70 is composed of about 50% w/w of propane, about 20% w/wof isobutane and about 30% w/w of propane. Hydrofluorocarbon (HFC)propellants are also suitable as propellants in the context disclosedherein. Exemplary HFC propellants include 1,1,1,2 tetrafluorethane(Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). Dimethylether is also useful. In one or more embodiments use of compressed gases(e.g., air, carbon dioxide, nitrous oxide, and nitrogen) is alsopossible.

In one or more embodiments a combination of at least two propellants,selected from HFC, hydrocarbon propellants, dimethyl ether andcompressed gases is contemplated.

Any concentration of the propellant, which affords an acceptable foam isuseful in accordance with the present invention. In certain embodimentsthe propellant makes up between about 3% by weight and about 25% byweight of the foamable composition, or between about 20% by weight andabout 30%, or between about 20% by weight and about 35% by weight andpreferably between about 5% by weight and about 16% by weight of thecomposition. $ In preparing the formulations the ingredients other thanpropellant are combined to 100% and the propellant is added thereafterso that the ratio of formulation to propellant can range from 100:3 to100:35, 100:3 to 100:30, 100:3 to 100:25 or preferably 100:5 to 100:16.

In one or more embodiments the propellant can also be used to expelformulation using a bag in can system or a can in can system as will beappreciated by someone skilled in the art. In certain embodiments thepart of the propellant system is in the formulation and part separatefrom the formulation. In this way it is possible to reduce the amount ofpropellant in the formulation but still provide good expulsion from thecanister, where the foamable formulation is expelled quickly but withoutjetting or noise. In one or more embodiments such system is used toexpel foam into a body cavity where the amount of propellant releasedinto the cavity is minimized.

Without being bound to any theory, it can be supposed that in certainembodiments in the absence of an independent oil phase, hydrocarbonpropellant is partially solubilized by the SCA and the fatty alcoholsand or fatty acids present in the composition, thus providing a clearcomposition. It was noted from a visual impaction that the fatty acidsand alcohols were dissolved in the composition.

Suspensions

In one or more embodiments the active or cosmetic ingredient iscompletely soluble in the formulation or a phase thereof. In certainother embodiments it is provided as a suspension. For example, benzylperoxide (‘BPO’) or microsponges comprising an active ingredient such asretinoic acid or other encapsulated bodies, such as described herein.The following description applied to BPO will also apply with thenecessary changes to other solid agents, microspheres and other bodies.As can be appreciated, forming a homogeneous suspension of a BPO orother solid particle or body in foamable formulation using a formulationwith high viscosity—so that even after addition of propellant theformulation has high viscosity—in order to try and stabilize the oildroplets and BPO particles, minimize particle motion and discouragegravitational sedimentation in the canister in which the formulation isstored simply will not do for foamable compositions. Such viscousformulations are not desirable for foamable compositions since they havelow flowability and may exhibit one or more of the following: are notshakable; form a block, i.e., a solid with no flowable mass, in thecanister; do not result in uniform expulsion; and if expulsed may beaccompanied by unwanted phenomena such as one or more of jets, tailingand noise.

Unexpectedly it has been discovered that it is possible to makecompositions which are truly flowable and have low viscosity in whichthe propellant forms part of the oil phase of the emulsion formulationbut nevertheless surprisingly does not make the formulationsubstantially vulnerable to phase separation and or sedimentation.Moreover these compositions are stable and are able to form breakablefoam of quality that spreads easily and is able to deliver an effectiveand measurable amount of active agent homogeneously to a target surface.

Optional Ingredients

A further element and aid to reducing viscosity in the presence of smallamounts of gelling agents is the use of a buffer or buffer complex, suchas citrate buffer or alternatively lactate to cause a thick emulsion gelor paste containing carbomer to become fluid. Other similar buffers maywork. Non limiting examples of appropriate possible buffers, which mayachieve the same objective are acetate, malate, sorbate, succinate andtartrate.

Optionally, the foamable composition further includes at least oneorganic carrier selected from the group consisting of a polar solvent, ahydrophobic organic carrier and mixtures thereof, at a concentration ofabout 2% to about 50% by weight.

Hydrophilic Solvent

A hydrophilic solvent is a solvent that is more miscible with water thanwith a hydrophobic compound.

Examples of suitable hydrophilic solvents are, propylene glycol, lowmolecular weight polyethylene glycols, methoxyisopropanol, PPG-2 propylether, PPG-2 butyl ether, PPG-2 methyl ether, PPG-3 methyl ether,dipropylene glycol propyl ether, dipropylene glycol butyl ether,dipropylene glycol, methyl propanediol, propylene carbonate, watersoluble/dispersible polypropylene glycols, ethoxylated polypropyleneglycol, glycerin, sorbitol, hydrogenated starch hydrolysate, siliconeglycols, and their mixtures and the like. In one or more embodimentswater is a hydrophilic solvent.

In one or more embodiments, the composition comprises a hydrophilicsolvent.

In one or more embodiments, the short chain alcohol is replaced by ahydrophilic solvent.

In one or more embodiments, the hydrophilic solvent is a polyol. Apolyol is an organic substance that contains at least two hydroxy groupsin its molecular structure. In one or more embodiments, the foamablecarrier contains at least one diol. In one or more embodiments, thefoamable carrier contains at least one triol. In one or moreembodiments, the polyol is a mixture of polyols. In one or moreembodiments, the mixture of polyols contains at least one diol and atleast one triol. In one or more embodiments the hydrophilic solvent is apolar solvent.

In one or more embodiments, the hydrophilic solvent is selected from thegroup consisting of propylene glycol, low molecular weight polyethyleneglycols and glycerin.

Polar Solvent

A “polar solvent” is an organic solvent which is typically soluble inboth water and oil.

In one or more embodiments, the polar solvent is a polyol. Polyols areorganic substances that contain at least two hydroxy groups in theirmolecular structure.

In one or more embodiments, the polar solvent contains an diol (acompound that contains two hydroxy groups in its molecular structure),such as propylene glycol (e.g., 1,2-propylene glycol and 1,3-propyleneglycol), butanediol (e.g., 1,4-butaneediol), butanediol (e.g.,1,3-butaneediol and 1,4-butenediol), butynediol, pentanediol (e.g.,1,5-pentanediol), hexanediol (e.g., 1,6-hexanediol), octanediol (e.g.,1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol, diethyleneglycol, triethylene glycol, tetraethylene glycol, dipropylene glycol anddibutylene glycol.

In one or more embodiments, the polar solvent contains a triol (acompound that contains three hydroxy groups in its molecular structure),such as glycerin and 1,2,6-Hexanetriol.

Additional examples of polar solvents include polyols, such as glycerol(glycerin), propylene glycol, hexylene glycol, diethylene glycol,propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol,other glycols, alkanols, such as dialkylamino acetates, and admixturesthereof, dimethyl isosorbide, ethyl proxitol, dimethylacetamide (DMAc)and alpha hydroxy acids, such as lactic acid and glycolic acid.

According to still other embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200 (MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof.

Yet, in additional embodiments, the polar solvent is an aprotic polarsolvents, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF),acetonitrile, acetone, methyl ethyl ketone, 1,4-Dioxane andtetrahydrofuran (THF). Additional non-limiting examples includeN-methylpyrrolidone, pyridine, piperidine, dimethyl ether,hexamethylphosphorotriamide, dimethylformanide, methyl dodecylsulfoxide, N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone) andazone (1-dodecylazacycloheptan-2-one).

Many polar solvents, for example propylene glycol, glycerin, DMSO andazone possess the beneficial property of a dermal, transdermal ortrans-mucosal drug delivery enhancer.

In one or more embodiments, the polar solvent is a dermal, transdermalor trans-mucosal drug delivery enhancer.

Many polar solvents, for example propylene glycol and glycerin, possessthe beneficial property of a humectant.

In one or more embodiments, the polar solvent is a humectant.

Hydrophobic Solvent/Emollient

One or more hydrophobic solvents are optionally included in thecomposition, in order to add to the sensory properties of thecomposition and/or in order to impart skin conditioning properties. Inan embodiment, the hydrophobic solvent is an emollient, i.e., asubstance that softens and soothes the skin. Emollients are used tocorrect dryness and scaling of the skin. The hydrophobic solvent and/orthe emollient can be selected from the group consisting of mineral oil,alkyl esters of fatty acids such as isopropyl palmitate, isopropylisostearate, diisopropyl adipate, diisopropyl dimerate, octyl palmitate,cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolinalcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryllinoleate, wheat germ glycerides, arachidyl propionate, myristyllactate, decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityltetrastearate, neopentylglycol dicaprylate/dicaprate, isononylisononanoate, isotridecyl isononanoate, myristyl myristate, triisocetylcitrate, octyl dodecanol, maleated soybean oil, unsaturated orpolyunsaturated oils, such as olive oil, corn oil, soybean oil, canolaoil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seedoil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil,salmon oil, flaxseed oil, wheat germ oil, evening primrose oils;essential oils; and silicone oils, such as dimethicone, cyclomethicone,polyalkyl siloxane, polyaryl siloxane, polyalkylaryl siloxane, apolyether siloxane copolymer and apoly(dimethylsiloxane)-(diphenyl-siloxane) copolymer. In certainembodiments the carrier can comprise a petrolatum where it is providedin modest or minor amounts of up to about 5%.

In one or more preferred embodiments the hydrophobic solvent has atleast a degree of solubility in the SCA present in the formulation.

In order to improve the miscibility or the dispersion of a hydrophobicsolvent in the formulation, fatty alcohols and preferably fatty acidscan be added in order to form an emulsion which is either stable oreasily re-dispersible by shaking. In certain embodiments small amountsof polymeric agents may be added up to about 0.2%. By re-dispersible onshaking is meant that the formulation on reasonable moderate shaking ofabout a few times will provide a uniform emulsion which will remainrelatively stable for at least a reasonable short period of timesufficient to allow it to be dispensed from the pressurized canister. Inone or more embodiments a combination of one or more fatty acids withone or more fatty alcohols is used to help provide an emulsion which hasat least a short term stability and is easily redispersable on shaking.

Modulating Agent

In one or more embodiments the formulation includes a modulating agent.The term modulating agent is used to describe an agent which can improvethe stability of or stabilize a foamable carrier or composition and oran active agent by modulating the effect of a substance or residuepresent in the carrier or composition.

In one or more embodiments the substance or residue may for example beacidic, basic or a buffer agent, which can affect pH in a composition.The agent can be any of the known buffering systems used inpharmaceutical or cosmetic formulations as would be appreciated by a manof the art. It can also be an organic acid, a carboxylic acid, a fattyacid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid anorganic base or a nitrogen containing compound. In certain embodimentsthe modulating agent is a buffer, as defined by Van Slyke [Van Slyke, J.Biol. Chem. 52, 525 (1922)], as “a substance which by its presence insolution increases the amount of acid or alkali that must be added tocause unit change in pH.”

Certain active agents are known to be stable at a narrow pH range. Forexample, corticosteroids are typically stable at acidic pH levels, whilevitamin D3 derivatives are stable at basic pH. Hence, in certainembodiments the modulating agent is selected to exert a pH modifyingeffect, which results in the desirable pH level.

In certain embodiments, the pH modifying agent is selected from thegroup including citric acid and sodium citrate.

It is important to maintain skin surface pH in order to preventsusceptibility to bacterial skin infections or skin damage and disease.Thus, adding a modulating agent, which contributes to the stabilizationof skin pH at the desirable level, is advantageous.

In the same fashion, adding an acidic modulating agent to a foamablecomposition, which is intended for vaginal application is advantageous,since better protection against vaginal infection is attained with pHlower than about 4.5.

In an embodiment, the modulating agent is an antioxidant or a radicalscavenger. Non-limiting examples of antioxidants/radical scavengers areascorbic acid and derivatives, tocopherol or derivatives thereof(succinate, or sorbate or acetate or other esters), propyl galate,butylated hydroxy toluene and butyl hydroxy anisol. Non-limitingexamples of positive ionization agents are benzyl conium chloride, andcetyl pyridium chloride. Non-limiting examples of negative ionizationagents are sodium lauryl sulfate, sodium lauryl lactylate andphospholipids.

In one or more further embodiments the modulating agent is a chelatingor sequestering or complexing agent that is sufficiently soluble orfunctional in the solvent to enable it to “mop up” or “lock” metal ions.In one or more embodiments a preferred non limiting example is EDTA.

Modulating agents may be added to the compositions of the subjectinvention, as necessary to provide their function of improving thestability of or stabilize a foamable carrier or composition and or anactive agent. The modulating agent concentration can preferably rangefrom about 0.1% to about 10%, more preferably from about 1% to about 5%,of the composition. In certain cases the active agent itself is themodulating agent, alone or in combination with another modulating agent,and in such cases it will be added at an effective dose which may beoutside these ranges. For example azelaic acid may be at about 15% byweight of the composition.

Additional Components

In an embodiment, a composition disclosed herein includes one or moreadditional components. Such additional components include but are notlimited to anti perspirants, anti-static agents, bulking agents,cleansers, colorants, skin conditioners, deodorants, diluents, dyes,fragrances, hair conditioners, herbal extracts, humectants, keratolyticagents, pearlescent aids, perfuming agents, pH preservatives,protectants, skin penetration or permeation enhancers, softeners,solubilizers, sunscreens, sun blocking agents, sunless tanning agents,viscosity modifiers, flavanoids and vitamins. As is known to one skilledin the art, in some instances a specific additional component may havemore than one activity, function or effect.

In one or more further embodiments the composition further includesabout 0.1% to about 5% of a humectant. In one or more furtherembodiments the humectant is selected from the group consisting of PEG400, propylene glycol and glycerin or mixtures of two or more thereof.

Substantially Surfactant Free

According to one or more embodiments, the foamable composition issubstantially surfactant-free. In the context herein, the term“substantially surfactant free composition” relates to a compositionthat contains a total of less than about 0.2% of a surfactant selectedfrom the group consisting of non-ionic, anionic, cationic, zwitterionic,amphoteric and ampholytic surfactants. Preferably, the compositioncomprises less than about 0.2% by weight by weight of a surfactant andmore preferably less than about 0.1%. Non-surfactant compositions willcomprise no or negligible levels of surface active agents (essentiallysurfactant free). In some embodiments, the foamable composition containsbetween about 0% and 0.2% surfactant, or between about 0% and 0.1%surfactant.

In the art, the term surface active agent or surfactant is sometimesused loosely and some publications may refer to compounds that have asupportive role, such as co-surfactants as surfactants. Substances whichcannot function as true surfactants on their own but only in the contextof being used with a surfactant are not considered to be surfactants forthe purposes described herein. Thus, in the context herein, a fattyalcohol is not regarded a surfactant, and likewise, a fatty acid is notregarded as a surfactant In contrast, however, an ether or an esterformed from them can be a surfactant. Also quaternary ammonium compoundsand ions, which for example are not infrequently seen in hairpreparations, are not regarded as surfactants.

Substantially Polymer Free

According to one or more embodiments, the foamable composition issubstantially polymeric agent free. In the context herein, the term“substantially polymeric agent free composition” relates to acomposition that contains a total of less than about 0.2% by weight of apolymeric agent selected from the group consisting of a bioadhesiveagent, a gelling agent, a film forming agent and a phase change agent,being locust bean gum, sodium alginate, sodium caseinate, egg albumin,gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seedextract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guargum, starch, amine-bearing polymers such as chitosan; acidic polymersobtainable from natural sources, such as alginic acid and hyaluronicacid; chemically modified starches and the like, carboxyvinyl polymers,polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers,polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinylchloride polymers, polyvinylidene chloride polymers, semi-syntheticpolymeric materials such as cellulose ethers, such as methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer(homopolymer of acrylic acid is crosslinked with an allyl etherpentaerythritol, an allyl ether of sucrose, or an allyl ether ofpropylene); poloxamers (synthetic block copolymer of ethylene oxide andpropylene); polyethylene glycol having molecular weight of 1000 or more(e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000) and which couldfunction as a hydro alcoholic foam booster. Preferably, the compositioncomprises less than about 0.1% by weight by weight of a polymeric agentand more preferably less than about 0.05%. Non-polymeric agentcompositions i.e. essentially polymeric agent free compositions willcomprise no or negligible levels of polymeric agents. According to oneor more embodiments, the foamable composition is essentially polymericagent free. In some embodiments, the foamable composition containsbetween 0% and 0.2% polymeric agent, between 0% and 0.1% polymericagent, or between 0% and 0.05% polymeric agent. In some embodiments, thefoamable composition contains between 0.05% and 0.2% polymeric agent, orbetween 0.05% and 0.1% polymeric agent, or between 0.1% and 0.2%polymeric agent.

In the art, the term polymeric agent can be used loosely to refer to anypolymer. However, polymers that do not have a hydro-alcoholic foamboosting role but may act in other ways, for example polyethyleneglycols, such as PEG 400, which are liquid hydrophilic polymericsolvents, are not excluded from the compositions. Similarly a polyethersiloxane copolymer and a poly(dimethylsiloxane)-(diphenyl-siloxane)copolymer and the like, which can provide a good feeling to thecomposition are not excluded. Also particles made of polymericsubstance, such as is microcapsules, microspheres, nanocapsules,nanospheres, polymer matrix, silica-gel, and microsponges are notexcluded from the compositions. Further polymeric active agents are notexcluded from the composition.

Physical Characteristics of the Foamable Composition and Foam

A foamable composition manufactured according to one or more embodimentsherein is very easy to use. When applied onto the afflicted body surfaceof mammals, i.e., humans or animals, it is in a foam state, allowingfree application without spillage. Upon further application of amechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

In one or more embodiments the foamable composition is a single phasesolution. In certain circumstances, where the active agent is insolubleand is presented as a homogenous suspension and the formulation isturbid or cloudy. In one or more other embodiments the formulation priorto addition of propellant is an emulsion. In one or more embodiments thefoam composition has an acceptable shelf-life of at least one year, orat least two years at ambient temperature. A feature of a product forcosmetic or medical use is long term stability. Propellants, which are amixture of low molecular weight hydrocarbons, tend to impair thestability. The foamable compositions herein are surprisingly stable,even in the absence of customary surfactants. Surprisingly they alsoform stable breakable foams even in the absence of customary polymericagents.

Following accelerated stability studies, they demonstrate desirabletexture; they form fine bubble structures that do not break immediatelyupon contact with a surface, spread easily on the treated area andabsorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam. Compositions containing a substantial amount ofsemi-solid hydrophobic solvents, e.g., white petrolatum, as the mainingredients of the oil phase of the emulsion, will likely exhibit highviscosity and poor flowability and are inappropriate candidates for afoamable composition.

Foam Quality

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

Foam Density

Another property of the foam is specific gravity or density, as measuredupon release from the aerosol can. Typically, foams have specificgravity of less than 0.20 g/mL or less than 0.12 g/mL, depending ontheir composition and on the propellant concentration.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. Shakability is describedfurther in the section on Tests. In one or more certain limitedembodiments the formulation is poorly shakable but is neverthelessflowable.

Breakability/Collapse Time

A further aspect of the foam is breakability. The balance betweenstability and breakability of the foam coming out of the container isvery delicate: on one hand the foam should preferably not be “quickbreaking”, i.e., it should be stable upon release from the pressurizedcontainer and not break as a result of exposure to skin temperature; andon the other hand, it should be “breakable”, i.e., it should spreadeasily, break down and absorb into the skin or membrane upon applicationof mild shear force. The breakable foam is thermally stable, yet breaksunder shear force. Sheer-force breakability of the foam is clearlyadvantageous over thermally-induced breakability. Thermally sensitivefoams start to collapse immediately upon exposure to skin temperatureand, therefore, cannot be applied on the hand and afterwards deliveredto the afflicted area.

The collapse time of foam represents its tendency to betemperature-sensitive and its ability to be at least short term stableso as to allow a user sufficient time to comfortably handle and applythe foam to a target area without being rushed and or concerned that itmay rapidly collapse, liquefy and or disappear. Collapse time, as anindicator of thermal sensitivity, is examined by dispensing a givenquantity of foam and photographing sequentially its appearance with timeduring incubation at 36° C.

Short chain alcohols are known to cause foam to be thermolabile and“quick breaking”. However, in certain embodiments herein, despite thepresence of high alcohol content, quite unexpectedly the foam issubstantially thermally stable. By “substantially thermally stable” itis meant that the foam upon application onto a warm skin or body surfaceat about 35-37° C. does not collapse within about 30 seconds. Thus, inone or more embodiments the simple collapse time of the foam is morethan about 30 seconds or more than about one minute or more than abouttwo minutes. In one or more limited embodiments simple collapse time canbe a little shorter than 30 seconds, but not less than about 20 seconds.In one or further or alternative embodiments the collapse time ismeasured by introducing a sample of foam into an incubator at 36 ° C.and the collapse time of the foam is more than 30 seconds or more thanabout one minute or more than about two minutes.

Pharmaceutical Composition

The foamable composition is an ideal vehicle for active pharmaceuticalingredients and active cosmetic ingredients. In the context activepharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents”. In one or moreembodiments the active agent is soluble in the composition of a phasethereof. In one or more other embodiments it is insoluble. Wheninsoluble the active agent is presented as a suspension or on a carrierwhich can include microspheres and the like.

Suitable active agents include but are not limited to an active herbalextract, an acaricides, an age spot and keratose removing agent, anallergen, an alpha hydroxyl acid, an analgesic agent, an antiacne agent,an antiallergic agent, an antiaging agent, an antibacterial agent, anantibiotic, an antiburn agent, an anticancer agent, an antidandruffagent, an antidepressant, an antidermatitis agent, an antiedemic anent,an antifungal agent, an antihistamine, an antihelminth agent, anantihyperkeratolyte agent, an anti-infective agent, an antiinflammatoryagent, an antiirritant, an antilipemic agent, an antimicrobial agent, anantimycotic agent, an antioxidant, an antiparasitic agent, anantiproliferative agent, an antipruritic agent, an antipsoriatic agent,an antirosacea agent, an antiseborrheic agent, an antiseptic agent, anantiswelling agent, an antiviral agent, an anti-wart agent, ananti-wrinkle agent, an antiyeast agents, an astringent, a beta-hydroxyacid, benzoyl peroxide, a topical cardiovascular agent, achemotherapeutic agent, a corticosteroid, an immunogenic substance, adicarboxylic acid, a disinfectant, a fungicide, a hair growth regulator,a haptene, a hormone, a hydroxy acid, an immunosuppressant, animmunoregulating agent, an immunomodulator, an insecticide, an insectrepellent, a keratolytic agent, a lactam, a local anesthetic agent, alubricating agent, a masking agent, a metal, a metal oxide, a mitocide,a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a protein, a photodynamic therapyagent, a radical scavenger, a refatting agent, a retinoid, a sanative, ascabicide, a self tanning agent, a skin protective agent, a skinwhitening agent, a steroid, a steroid hormone, a vasoconstrictor, avasodilator, a vitamin, a vitamin A, a vitamin A derivative, a vitaminB, a vitamin B derivative, a vitamin C, a vitamin C derivative, avitamin D, a vitamin D derivative, a vitamin D analog, a vitamin F, avitamin F derivative, a vitamin K, a vitamin K derivative, a woundhealing agent and a wart remover. As is known to one skilled in the art,in some instances a specific active agent may have more than oneactivity, function or effect.

Encapsulation of an Active Agent

In one or more embodiments, the active agent is encapsulated inparticles, microparticles, nanoparticles, microcapsules, microspheres,nanocapsules, nanospheres, liposomes, niosomes, polymer matrix,silica-gel, graphite, nanocrystals or microsponges. Such particles canhave various functions, such as (1) protection of the drug fromdegradation; (2) modification of the drug release rate from thecomposition; (3) control of skin penetration profile; and (4) mitigationof adverse effects, due to the controlled release of the active agentfrom the encapsulation particles.

Solubility of an Active Agent

In an embodiment, the active agent is not fully soluble in water or, isnot fully soluble in the SCA, is not fully soluble in the presence of ahydrophobic solvent in the formulation, or is not fully soluble in theoil phase of the emulsion. In one or more embodiments the active agentis soluble in the composition or a phase thereof. In an embodiment, theaprotic polar solvent is present in the composition in an amountsufficient to solubilize the active agent in the composition. In one ormore embodiments, aprotic polar solvent acts to improve the solubilityof an active agent. In certain preferred embodiments, the active agentto be solubilized is selected from the group consisting of anon-steroidal anti-inflammatory agent, a local anesthetic agent, asteroid, an immunomodulators, a keratolytically active agent, ananti-acne agent, an anti-rosacea agent, an antiinfective agent and ananti-psoriasis agent. In a preferred embodiment the active agent to besolubilized is diclofenac.

Exemplary Groups of Active Agents Steroids

In an embodiment, the active agent is a steroid. In certain embodimentsthe steroid is a corticosteroid, including but not limited to,bydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone valerate and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, aswell as analogs, derivatives, salts, ions and complexes thereof.

In certain embodiments, the steroid is a hormone or a vitamin, asexemplified by pregnane, cholestane, ergostane, aldosterone,androsterone, calcidiol, calciol, calcitriol, calcipotriol,clomegestone, cholesterol, corticosterone, cortisol, cortisone,dihydrotestosterone, ergosterol, estradiol, estriol, estrone,ethinylestradiol, fusidic acid, glucocorticoid, lanosterol, mometasonefuroate, prednisolone, prednisone, progesterone, spironolactone,timobesone and testosterone, as well as analogs, derivatives, salts,ions and complexes thereof.

In an embodiment, the aprotic polar solvent is present in thecomposition in an amount sufficient to solubilize the steroid.

NSAID

In an embodiment, the active agent is a non-steroidal anti-inflammatoryagent. In the context a nonsteroidal antiinflammatory agent (also termedherein “NSAID”) is a pharmaceutically active compound, other than acorticosteroid, which affects the immune system in a fashion thatresults in a reduction, inhibition, prevention, amelioration orprevention of an inflammatory process and/or the symptoms ofinflammation and or the production pro-inflammatory cytokines and otherpro-inflammatory mediators, thereby treating or preventing a diseasethat involves inflammation.

In one or more embodiments, the NSAID is an inhibitor of thecyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are knowntoday: the constitutive cyclooxygenase (COX-1); and the induciblecyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or moreembodiments, the NSAID is selected from the group consisting of a COX-1inhibitor, a COX-2 inhibitor or a non-selective NSAID, whichsimultaneously inhibits both COX-1 and COX-2.

In one or more embodiments, the NSAID is salicylic acid a salicylic acidderivatives. Exemplary salicylic acid derivative include, in a nonlimiting fashion, aspirin, sodium salicylate, choline magnesiumtrislicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine, olsalazine, esters of salicylic acid with a carboxylicacid, esters of salicylic acid with a dicarboxylic acid, esters ofsalicylic acid with a fatty acid, esters of salicylic acid with ahydroxyl fatty acid, esters of salicylic acid with an essential fattyacid, esters of salicylic acid with a polycarboxylic acid, and anycompound wherein salicylic acid is linked to an organic moiety through acovalent bond.

In one or more embodiments, the NSAID is para-aminophenol (e.g.,acetaminophen) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an indole or an indole—aceticacid derivative (e.g., indomethacin, sulindac, etodolac) and salts andderivatives thereof.

In one or more embodiments, the NSAID is an aryl acetic acids (e.g.,tolmetin, diclofenac, ketorolac) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an arylpropionic acid and saltsand derivatives thereof. Exemplary arylpropionic acid derivativeinclude, in a non limiting fashion, are ibuprofen, naproxen,flubiprofen, ketoprofen, fenoprofen, oxaprozin.

In one or more embodiments, the NSAID is anthranilic acids or ananthranilic acid derivative, also termed “fenamates” (e.g., mefenamicacid, meclofenamic acid) and salts and derivatives thereof.

In one or more embodiments, the NSAID is selected from the group ofenolic acids, enolic acid salts, enolic acid esters, amides, anhydridesand salts and derivatives thereof. Non-limiting examples of enolic acidderivatives include oxicams (piroxicam, tenoxicam) andpyrazolidinediones (phenylbutazone, oxyphenthratrazone)

Yet, in additional embodiments, the NSAID is an alkanone (e.g.,nabumetone).

Selective COX-2 Inhibitors include, in an exemplary mannerdiaryl-substituted furanones (e.g., Rofecoxib); diaryl-substitutedpyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac); andsulfonanilides (e.g., Nimesulide) and salts and derivatives thereof.

In an embodiment, the aprotic polar solvent is present in thecomposition in an amount sufficient to solubilize the NSAID, asexemplified herein by the solubilization of diclofenac.

Local Anesthetic Agents

In an embodiment, the active agent is a local anesthetic agent. Withoutlimiting the scope, the anesthetic agent can be selected from the groupconsisting of benzocaine, lidocaine, bupivacaine, chlorprocaine,dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine,procaine, cocaine, ketamine, pramoxine, phenol, any pharmaceuticallyacceptable salts thereof and mixtures of such anesthetic agents. Anymixture of synergistically beneficial anesthetic agents is contemplated.In an embodiment, the aprotic polar solvent is present in thecomposition in an amount sufficient to solubilize the anesthetic agent.

Keratolytically Active Agents

A keratolytic agent may be included as an active agent of a foamablecomposition. The term “keratolytically active agent” as used hereinincludes a compound that loosens and removes the stratum corneum of theskin, or alters the structure of the keratin layers of skin.Keratolytically active agents are used in the treatment ofdermatological disorders that involve dry skin, hyperkeratinization(such as psoriasis), skin itching (such as xerosis), acne and rosacea.

Suitable keratolytically active agents include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. As such, they areused in the treatment of dermatological disorders. Dihydroxybenzene andderivatives thereof have been recognized as potent keratolytic agents.Resorcinol (m-dihydroxybenzene) and derivatives thereof are used inanti-acne preparations. In addition to hydroquinone (p-dihydroxybenzene)having anti-pigmentation properties, hydroquinone is also known to bekeratolytic. These compounds also exhibit antiseptic properties. Cresolsalso possess bactericidal and keratolytic properties.

Vitamin A and vitamin A derivatives, also termed herein “retinoids”,such as retinoic acid, isoretinoic acid, retinol and retinal, as well asadapalene, tazarotene, isotretinoin, acitretin and additional retinoidsknown in the art of pharmaceuticals and cosmetics are another class ofkeratolytically active agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as salicylic acid(o-hydroxybenzoic acid) and salicylic acid salts and pharmaceuticallyacceptable derivatives.

Another class of keratolytically active agents includes urea and ureaderivatives.

Immunomodulators

In an embodiment, the active agent is an immunomodulatorImmunomodulators are chemically or biologically-derived agents thatmodify the immune response or the functioning of the immune systemImmunomodulators suitable for use according to the present inventioninclude, among other options, cyclic peptides, such as cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus,laquinimod and imiquimod, as well as analogs, derivatives, salts, ionsand complexes thereof. Such compounds, delivered in the foam, areespecially advantageous in skin disorders such as psoriasis, eczema andatopic dermatitis, where the large skin areas are to be treated. In anembodiment, the aprotic polar solvent is present in the composition inan amount sufficient to solubilize the immunomodulator.

Retinoids

In an embodiment, the active agent is a retinoid. Retinoids suitable foruse according to the present invention include, among other options,retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene,13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene,lycopene, 9-cis-beta-carotene, lutein and zeaxanthin, as well as anyadditional retinoids known in the art of pharmaceuticals and cosmetics;and analogs, derivatives, salts, ions and complexes thereof.

Anti-Acne and Anti-Rosacea Active Agents

In an embodiment, the active agent is an anti-acne or an anti-rosaceaagent. The anti-acne agent can be selected from the group consisting ofresorcinol, sulfur, salicylic acid and salicylates, alpha-hydroxy acids,nonsteroidal anti-inflammatory agents, benzoyl peroxide, retinoic acid,isoretinoic acid and other retinoid compounds, adapalene, tazarotene,azelaic acid and azelaic acid derivatives, antibiotic agents, such aserythromycin and clyndamycin, coal tar, zinc salts and complexes, andcombinations thereof, in a therapeutically effective concentration.

Antipsoriasis Agents

In an embodiment, the active agent is an anti-psoriasis agent. Suchanti-psoriasis agent can be selected, among other options, from thegroup of keratolytically-active agents, salicylic acid, coal tar,anthralin, corticosteroids, vitamin D and derivatives and analogsthereof, including vitamin D3 analogs such as calcitriol, calcipotriol;retinoids, and photodymamic therapy agents.

Antiinfective Agents

In an embodiment, the active agent is an anti-infective agent. Suchanti-infective agent can be selected from the group of an antibioticagent, an antibacterial agent, an antifungal agent, an agent thatcontrols yeast, an antiviral agent and an antiparasitic agent. Exemplaryantiinfective agents are exemplified by beta-lactam antibiotic, anaminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole,metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin,clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxinB, an antibiotic polyene, an antibiotic polyether, an antibioticquinolone, an antibiotic steroid, fucidic acid, mupirocin,chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal,silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, anoxidizing agent, iodine, iodate, a periodate, a hypochlorite, apermanganate, a substance that release free radicals and/or activeoxygen, a cationic antimicrobial agent, a quaternary ammonium compound,a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymericbiguanide and a naturally occurring antibiotic compound, as well asanalogs, derivatives, salts, ions and complexes thereof.

The Foamable Composition Essential Ingredients as Active Agents

In certain embodiments, the short chain alcohol possesses therapeuticproperties on its own and therefore, it can be regarded as “activeagent”. For example, ethanol kills microorganisms and can be effectivein the treatment or prevention of conditions that involve microbialinfection, such as bacterial, fungal and viral conditions. Additionally,the defatting effect of alcohol is useful for the treatment ofconditions which involve oily skin, such as acne, Rosacea and seborrheicdermatitis. The combination of a short chain alcohol and atherapeutically effective fatty alcohol or fatty acid may afford asynergistic beneficial effect in conditions characterized, for example,by infection and/or inflammation.

Because short chain alcohols are known to increase the rate ofabsorption of some compounds through organic tissues including skin andnails, formulations comprising such alcohols can be used as a drugdelivery system.

Combination of Active Agents

Several disorders involve a combination of more than one etiologicalfactor; and therefore, the use of more that one active agents isadvantageous. For example, psoriasis involves excessive cellproliferation and inadequate cell differentiation as well asinflammation. Atopic dermatitis involves keratinocyte growthabnormality, skin dryness and inflammation. Bacterial, fungal and viralinfections involve pathogen colonization at the affected site andinflammation. Hence, in many cases, the inclusion of a combination ofactive agents in the foamable pharmaceutical composition can bedesirable. Thus, in one or more embodiments, the foamable compositionfurther includes at least two active agents, in a therapeuticallyeffective concentration.

Fields of Applications

The foamable composition is suitable for treating any inflicted surface.In one or more embodiments, foamable carrier is suitable foradministration to the skin, a body surface, a mucosal surface and a bodycavity, e.g., the cavity and/or the mucosa of the nose, mouth and eye,the ear, the respiratory system, the vagina or the rectum (severally andinterchangeably termed herein “target site”). The foamable compositionis suitable for use in the manufacture of a medicament for preventing ortreating a dermatological or a mucosal disorder.

By selecting a suitable active agent, or a combination of two or moreactive agents, the foamable composition is useful in treating an animalor a human patient having any one of a variety of dermatologicaldisorders, including dermatological pain, dermatological inflammation,acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acnefulminans, nodular papulopustular acne, acne conglobata, dermatitis,bacterial skin infections, fungal skin infections, viral skininfections, parasitic skin infections, skin neoplasia, skin neoplasms,pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas,cutaneous abscesses, necrotizing subcutaneous infections, scalded skinsyndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing moistens, gangrene, scarring, and vitiligo. The foamablecomposition is suitable for use in the manufacture of a medicament forpreventing or treating any of the preceding disorders.

Likewise, the foamable composition is suitable for treating a disorderof a body cavity or mucosal surface, e.g., the mucosa of the nose,mouth, eye, ear, respiratory system, vagina or rectum. Non limitingexamples of such conditions include chlamydia infection, gonorrheainfection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV),genital warts, bacterial vaginosis, candidiasis, chancroid, granulomaInguinale, lymphogranuloma venereum, mucopurulent cervicitis (MPC),molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis,vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvardystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis,pelvic inflammation, endometritis, salpingitis, oophoritis, genitalcancer, cancer of the cervix, cancer of the vulva, cancer of the vagina,vaginal dryness, dyspareunia, anal and rectal disease, analabscess/fistula, anal cancer, anal fissure, anal warts, Crohn's disease,hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation,polyps of the colon and rectum. The foamable composition is suitable foruse in the manufacture of a medicament for preventing or treating any ofthe preceding disorders.

In an embodiment the composition is useful for the treatment of aninfection. In one or more embodiments, the composition is suitable forthe treatment of an infection, selected from the group of a bacterialinfection, a fungal infection, a yeast infection, a viral infection anda parasitic infection. The foamable composition is suitable for use inthe manufacture of a medicament for preventing or treating any of thepreceding disorders.

In an embodiment the composition is useful for the treatment of wound,ulcer and burn. The foamable composition is suitable for use in themanufacture of a medicament for treating wounds, ulcers, and burns.

In an embodiment the target site is selected from the group consistingof the skin, a body cavity, a mucosal surface, the nose, the mouth, theeye, the ear canal, the respiratory system, the vagina and the rectum.

The composition is also suitable for administering a hormone to the skinor to a mucosal membrane or to a body cavity, in order to deliver thehormone into the tissue of the target organ, in any disorder thatresponds to treatment with a hormone. The foamable composition issuitable for use in the manufacture of a medicament to deliver thehormone into the tissue of the target organ, in any disorder thatresponds to treatment with a hormone.

In an embodiment the target site is selected from the group consistingof the skin, a body cavity, a mucosal surface, the nose, the mouth, theeye, the ear canal, the respiratory system, the vagina and the rectum.

In an embodiment the disorder is selected from the group consisting ofdermatological pain, dermatological inflammation, acne, acne vulgaris,inflammatory acne, non-inflammatory acne, acne fulminans, nodularpapulopustular acne, acne conglobata, dermatitis, bacterial skininfections, fungal skin infections, viral skin infections, parasiticskin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis,acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,necrotizing subcutaneous infections, scalded skin syndrome,folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing myositis, gangrene, scarring, and vitiligo, chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranuloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum; and whereinthe active agent is suitable for treating said disorder. The foamablecomposition is suitable for use in the manufacture of a medicament forpreventing or treating any of the preceding disorders

In one embodiment the disorder is an inflammation, skin inflammation,acne, rosacea, actinic keratosis, skin cancer, a local pain, joint painand ostheoarthritis; the active agent is a nonsteroidalanti-inflammatory drug, given at a therapeutically effectiveconcentration. The foamable composition is suitable for use in themanufacture of a medicament for preventing or treating any of thepreceding disorders. The foamable composition is suitable for use in themanufacture of a medicament including any of the preceding activeagents.

In one or more embodiments, the active agent may be a placebo or acosmetic agent. The foamable composition is suitable for use in themanufacture of a medicament including a placebo or active agent.

Cosmetic Use

In one or more embodiments, the composition may be used for cosmeticuse. For example it may be used as part of a cosmetic formulation toprevent a cosmetic disorder or to improve the skin. Alternatively it maybe used with cosmetic effect for example as a cosmetic remover. It canbe dispensed in small quantities as a foam targeted to a surface andapplied locally with mechanical force causing the foam to break.

EXAMPLES

The invention is described with reference to the following examples, ina non-limiting manner. The following examples exemplify the foamablecompositions and methods described herein. The examples are for thepurposes of illustration only and are not intended to be limiting. Manyvariations will suggest themselves and are within the full intendedscope.

Example 1 General Manufacturing Procedures

The following procedures are used to produce the foam samples describedin the examples below, in which only the steps relevant to eachformulation are performed depending on the type and nature ofingredients used.

Step 1: Ethanol and, if present, humectants are mixed at roomtemperature. Polymers or gelling agents, if present, are added at roomtemperature under mixing until formulation homogeneity is obtained.Surfactants and fatty alcohols or fatty acids, if present, are addedunder agitation until complete dissolution.

Step 2: Any pH-buffering agents are added to water at room temperatureunder mixing until complete dissolution.

Step 3: The alcoholic phase is added to the water phase under mixinguntil homogeneity is obtained.

Step 4: The formulation is packaged in aerosol canisters which arecrimped with a valve, pressurized with propellant and equipped with anactuator suitable for foam dispensing. Optionally a metered dosage unitcan be utilized to achieve delivery of repeatable measured doses offoam, for example as described in U.S. Provisional Application No.61/363,577 entitled “APPARATUS AND METHOD FOR RELEASING A UNIT DOSE OFCONTENT FROM A CONTAINER,” filed Jul. 12, 2010, which is incorporatedherein by reference.

Note: hydrophobic substances, if present, are added to the alcohol phasewith the fatty alcohols and or fatty alcohols.

Materials

TABLE 1 Exemplary possible ingredients suitable for the production offoamable compositions disclosed herein. Equivalent materials from othermanufacturers can also be used satisfactorily. Commercial Chemical NameFunction Name Supplier Acrylates/C10-30 Gelling agent Pemulen TR2 Noveonalkyl acrylate crosspolymer Behenyl alcohol Foam adjuvant Lanette 22Cognis Benzoyl Peroxide Active agent Benzoyl Peroxide SpectrumBetamethasone Active agent Betamethasone Crystal Valerate ValeratePharma Carbomer 934P Gelling agent Carbopol 934P Spectrum Cetostearylalcohol Foam adjuvant Speziol C16-C18 Cognis Cetyl alcohol Foam adjuvantSpeziol C16 Cognis Citric acid pH modifying Citric acid R. de Haen agentClindamycin Active agent Clindamycin Uqifa Phosphate PhosphateCoco-betaine Surfactant Dehyton Cognis Diclofenac sodium Active agentDiclofenac Sriken sodium Ethanol absolute Solvent Ethanol Bio LabGlycerin Humectant Glycerin Cognis Hexylene Glycol Solvent HexyleneGlycol Spectrum Hydroxypropyl Gelling agent Klucel EF Hercules celluloseHydroxypropyl Gelling agent Methocel K100M Colorcon methylcellulose DowLaureth-23 Surfactant Brij 35P Uniqema Myristic acid Foam adjuvantMyristic acid Spectrum Myristyl alcohol Foam adjuvant Speziol C14 CognisOleth-20 Surfactant Samulsol 98 Seppic PEG-40 Stearate Surfactant Myrj52S Croda Poloxamer 407 Gelling agent Lutrol F127 BASF PolyethyleneHumectant PEG-400 Inoes glycol 400 Polysorbate 60 Surfactant Polysorbate60 Cognis Propane/Isobutane/ Propellant A-46 Aeropress Butane (16:82:2)Corporation Propane/Isobutane/ Propellant AP-70 Aeropress Butane(55:18:27) Corporation Propylene glycol Humectant Propylene Glycol GadotSodium citrate pH modifying Sodium Citrate Archer agent Daniels MildSodium lauryl Surfactant Lanette E PH Cognis sarcosinate Sodium LaurylSurfactant Sodium dodecyl Cognis Sulfate sulfate Stearic acid Foamadjuvant Stearic acid Spectrum Stearyl Alcohol Foam adjuvant Speziol C18Cognis Tetrafluoroethane Propellant Dymel 134a DuPont Triethanolamine pHmodifying TEA Gadot agent Xanthan Gum Gelling agent Xanthan Gum CP KelcoUS 11K

Production Under Vacuum

Optionally, the foamable carrier may be produced under nitrogen andunder vacuum. Whilst the whole process can be carried out under anoxygen free environment, it can be sufficient to apply a vacuum afterheating and mixing all the ingredients to obtain an emulsion orhomogenous liquid. Preferably the production chamber is equipped toapply a vacuum but if not the formulation can be for example placed in adesiccator to remove oxygen prior to filing and crimping.

Canisters Filling and Crimping

Each aerosol canister is filled with the pre-foam formulation (“PFF”,i.e., foamable carrier) and crimped with valve using vacuum crimpingmachine. The process of applying a vacuum will cause most of the oxygenpresent to be eliminated. Addition of hydrocarbon propellant may withoutbeing bound by any theory further help to reduce the likelihood of anyremaining oxygen reacting with the active ingredient. It may do so,without being bound by any theory, by one or more of dissolving in, tothe extent present, the oil or hydrophobic phase of the formulation, bydissolving to a very limited extent in the aqueous phase, by competingwith some oxygen from the formulation, by diluting out any oxygen, by atendency of oxygen to occupy the dead space, and or by oxygen occupyingpart of the space created by the vacuum being the unfilled volume of thecanister or that remaining oxygen is rendered substantially ineffectivein the formulation.

Pressurizing & Propellant Filling

Pressurizing is carried out using a hydrocarbon gas or gas mixture.Canisters are filled and then warmed for 30 seconds in a warm bath at50° C. and well shaken immediately thereafter.

Tests

By way of non-limiting example the objectives of hardness, collapse timeand freeze-thaw cycle (“FTC”) stability tests are briefly set out belowas would be appreciated by a person of the art.

Collapse Time

Collapse Time, which is the measure of thermal stability, is examined bydispensing a given quantity of foam and photographing sequentially itsappearance with time during incubation at 36° C. The collapse timeresult is defined as the time when the foam height reaches 50% of itsinitial height or if the foam has not yet reached 50% of its initialheight after say 180 seconds then the collapse time is recorded asbeing >180. By way of illustration one foam may remain at 100% of itsinitial height for three minutes, a second foam may reach 90% of itsinitial height after three minutes, a third foam may reach 70% of itsinitial height after three minutes, and a fourth foam may reach 51% ofits initial height after three minutes, nevertheless in each of thesefour cases the collapse time is recorded as >180 secs since forpractical purposes for easy application by a patient to a target themajority of the foam remains intact for more than 180 secs. If the foamfor example reaches 50% of its original height after say 100 seconds itwould be recorded as having a collapse time of 100 seconds. It is usefulfor evaluating foam products, which maintain structural stability atskin temperature for at least 1 minute. Foams which are structurallystable on the skin for at least one minute are termed “short termstable” carriers or foams.

Alternatively, a Simple Collapse Time can be assessed by placing a foamsample on the warm fingers of a volunteer and measuring the time ittakes to melt on the fingers, for example, as observed in Example 4herein.

Density

In this procedure, the foam product is dispensed into vessels (includingdishes or tubes) of a known volume and weight. Replicate measurements ofthe mass of foam filling the vessels are made and the density iscalculated. The canister and contents are allowed to reach roomtemperature. Shake the canister to mix the contents and dispense anddiscard 5-10 mL. Then dispense foam into a pre-weighed tube, filling ituntil excess is extruded Immediately remove (level off) excess foam atboth ends and weigh the filled tube on the weighing balance.

Viscosity

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜>50,000 CP, the viscosity at 1 RPM may be measured, although thefigures are of a higher magnitude. Unless otherwise stated viscosity ofthe pre-foam formulation (PFF) is provided. It is not practical to tryand measure the viscosity of the foamable formulation with regularpropellants since they have to be stored in sealed pressurized canistersor bottles. In order to simulate the viscosity in the foamableformulations with propellant an equivalent weight of pentane (a lowvolatile hydrocarbon) is added to and mixed with the pre-foamformulation and left overnight. The viscosity is then measured as above.

FTC (Freeze Thaw Cycles)

Foam appearance under extreme conditions of repeated heating and coolingis evaluated by cycling through cooling, heating, (first cycle) cooling,heating (second cycle) etc., conditions, commencing with −10° C. (24hours) followed by +40° C. (24 hours) and measuring the appearancefollowing each cycle. The cycle is repeated for up to three times.

Chemical Stability

The amount of active agent present is analyzed in foam expelled fromvarious pressurized canisters containing foam formulations using HPLC.Analysis is carried out at zero time and at appropriate time intervalsthereafter. The canisters are stored in controlled temperatureincubators at one or more of 5 C, at 25 C, at, 40 C and at 50 C. Atappropriate time intervals canisters are removed and the amount ofactive agent in the foam sample is measured.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubbles size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital cameraequipped with a macro lens. The diameter of about 30 bubbles is measuredmanually relatively to calibration standard template. Statisticalparameters such as mean bubble diameter, standard deviation andquartiles are then determined Measuring diameter may also be undertakenwith image analysis software. The camera used is a Nikon D4OX Camera(resolution 10MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mmF2.8 EX DG HSM). Pictures obtained are cropped to keep a squared regionof 400 pixels×400 pixels.

Microscope Size:

The light microscope enables observing and measuring particles from fewmillimeters down to one micron. Light microscope is limited by thevisible light wavelength and therefore is useful to measuring size ofparticles above 800 nanometers and practically from 1 micron (1,000nanometers).

Shakability

Shakability represents the degree to which the user is able to feel/hearthe presence of the liquid contents when the filled pressurized canisteris shaken. Shaking is with normal mild force without vigorous shaking orexcessive force. When the user cannot sense the motion of the contentsduring shaking the product may be considered to be non-shakable. Thisproperty may be of particular importance in cases where shaking isrequired for affecting proper dispersion of the contents.

Shakability Scoring:

Good shakability (conforms to required quality specification) 2 Moderateshakability (conforms to required quality specification) 1 Not shakable(fails to meet required quality specification) but may 0 still beflowable and allow foam formation of quality Is substantially not ableto pass through valve Block

Example 2 Hydro-Alcoholic Formulations Containing a Combination ofSurfactants and Polymers

Several surfactants were used in combination with gelling agents(polymers) and checked for their foaming properties.

As described in Table 2a below, formulations 1, 7, 8 and 12 containinglaureth-23 or oleth-20 non-ionic surfactants in combination with variouspolymers did not give rise to foams but merely generated bubbly liquids.

TABLE 2a Formulations containing laureth-23 or oleth-20 Formulation 1 78 12 % w/w % w/w % w/w % w/w Ingredient Ethanol 51.00 51.50 50.50 51.00Purified water 36.00 40.00 40.90 36.90 PEG 400 — — 5.00 5.00 Propyleneglycol 5.00 — — — Glycerin — 5.00 — — Hydroxypropyl cellulose — — 1.50 —Poloxamer 407 20% 5.00 — — 5.00 solution Carbomer 974 — 0.40 — —Triethanolamine — 0.10 — — Laureth-23 2.00 2.00 2.00 — Oleth-20 — — —2.00 Citric acid 0.40 0.40 0.07 0.07 Sodium citrate 0.60 0.60 0.03 0.03Total 100.00 100.00 100.00 100.00 Propellant AP-70 8.00 8.00 8.00 8.00Results Foam Quality Poor Poor Poor Poor Product Clarity Yes No Yes Yes

As described in Table 2b below, formulations 2, 5 and 11 containingpolysorbate 60 and PEG 40 stearate non-ionic surfactants in combinationwith various polymers did not give rise to foams but merely generatedbubbly liquids.

TABLE 2b Formulations containing polysorbate 60 and PEG 40 stearateFormulation 2 5 11 % w/w % w/w % w/w Ingredient Ethanol 50.50 51.5051.50 Purified water 40.00 40.00 40.90 PEG400 — — 5.00 Propylene glycol— 5.00 — Glycerin 5.00 — — Hydroxypropyl cellulose 1.50 — —Hydroxypropyl — 0.50 — methylcellulose Carbomer 974 — — 0.40Triethanolamine — — 0.10 Polysorbate 60 0.60 0.60 0.60 PEG 40 Stearate1.40 1.40 1.40 Citric acid 0.40 0.40 0.07 Sodium citrate 0.60 0.60 0.03Total 100.00 100.00 100.00 Propellant AP-70 8.00 8.00 8.00 Results FoamQuality Poor Poor Poor Product Clarity Yes Yes No

As described in Table 2c below, formulations 3, 9 and 10 containingsodium lauryl sulfate and coco-betaine (anionic and zwitterionicsurfactants) in combination with various polymers did not give rise tofoams but merely generated bubbly liquids.

TABLE 2c Formulations containing sodium lauryl sulfate and coco-betaineFormulation 3 9 10 % w/w % w/w % w/w Ingredient Ethanol 52.90 52.4051.90 Purified water 40.00 36.90 40.90 PEG 400 5.00 — — Propylene glycol— — 5.00 Glycerin — 5.00 — Hydroxypropyl cellulose — — 1.50 Poloxamer407 20% solution — 5.00 — Hydroxypropyl 0.50 — — methylcellulose Sodiumlauryl sulfate 0.30 0.30 0.30 Coco-betaine 0.30 0.30 0.30 Citric acid0.40 0.07 0.07 Sodium citrate 0.60 0.03 0.03 Total 100.00 100.00 100.00Propellant AP-70 8.00 8.00 8.00 Results Foam Quality Poor Poor PoorProduct Clarity Yes Yes Yes

As described in Table 2d below, formulations 17 and 18 containing sodiumlauryl sarcosinate and sodium cetearyl sulfate anionic surfactants incombination with various polymers did not give rise to foams but merelygenerated bubbly liquids.

TABLE 2d Formulations containing sodium lauryl sarcosinate and sodiumcetearyl sulfate Formulation 017 018 % w/w % w/w Ingredient Ethanol52.90 52.40 Purified water 40.90 36.90 PEG 400 5.00 — Glycerin — 5.00Poloxamer 407 20% solution — 5.00 Hydroxypropyl methylcellulose 0.50 —Sodium lauryl sarcosinate 0.30 0.30 Sodium cetearyl sulfate 0.30 0.30Citric acid 0.07 0.07 Sodium citrate 0.03 0.03 Total PFF components:100.00 100.00 Propellant AP-70 8.00 8.00 Results Foam Quality Poor PoorProduct Clarity Yes Yes

As described in Table 2e below, formulations 52, 53 and 54 containingpolymeric agents alone such as Hydroxypropyl cellulose (acellulose-based polymer), poloxamer 188 (a polymer having somesurfactant-like properties) and Acrylates/C10-30 alkyl acrylatecrosspolymer (an amphiphilic polymer said to have some emulsifying-likeproperties) did not give foams but bubbly liquids.

TABLE 2e Formulations containing various polymeric agents Formulation 5253 54 % w/w % w/w % w/w Ingredient Ethanol 50.00 50.00 50.00 Purifiedwater 47.00 47.00 47.00 Hydroxypropyl cellulose 3.00 — 1.50 Poloxamer188 — 3.00 — Acrylates/C10-30 alkyl acrylate — — 3.00 crosspolymer Total100.00 100.00 100.00 Propellant AP-70 8.00 8.00 8.00 Results FoamQuality Poor Poor Poor

This study shows that polymeric agents alone or combinations ofpolymeric agents one of which has some surfactant like properties arenot sufficient to achieve good foaming properties in case of water-basedvehicles containing large amounts of short chain alcohols.

Surfactant alone, polymer alone, surfactant plus polymer andcombinations of polymers, one of which has surfactant like propertiesall failed to produce a quality hydro-alcoholic foam. This is asurprising result considering that based on the prior art, surfactantsare known as useful foam boasting agents, especially when used incombination with polymeric agents. It appears that high levels of SCA'se.g. ethanol have an apparent defoaming effect or destabilizing effect,and thus it is not at all obvious how to obtain good quality foams withhigh levels of short chain alcohols.

Example 3 Hydro-Alcoholic Formulations Containing FGatty Alcohols and/orFatty Acids

The influence of fatty alcohols and fatty acids on the foamingproperties of hydro-alcoholic formulations was studied.

As described in Table 3 below, good quality foams can be obtained withfatty alcohol. Likewise, good quality foams can be achieved with certainfatty acids. For example formulation 40 containing stearic acid gave agood quality foam, whereas formulation 41 containing isostearic acidonly resulted in a bubbly liquid. Without being bound by any theoryisostearic acid, which is non linear and liquid in contrast to stearicacid being linear and solid and may generate some steric hindrance andlower viscosity. Thus, the present invention is not limited to fattyalcohols and fatty alcohol combinations but includes also the use offatty acids and fatty acid combinations as stabilizing agents inhydro-alcoholic foams alone or in combination with fatty alcohols (seee.g. example 9). All the formulations were surprisingly successful inthe absence of a customary surfactant and in the absence of a customarypolymeric agent

To evaluate the possible importance of the carbon chain length on thefoaming properties of hydro-alcoholic formulations, several fattyalcohols containing from 14 to 22 carbons were used to create foams.Surprisingly, fatty alcohols comprising 14 carbons (myristyl alcohol) or22 carbons (behenyl alcohol) on their own only produced bubbly liquidsas shown in formulations 42 and 45. However, fatty alcohol having acarbon chain length of 16 to 18 gave foams of fairly good to excellentquality. For example, cetyl alcohol (C16) provided fairly good qualityfoam and stearyl alcohol gave good quality foams, as shown informulations 43 and 44. Very surprisingly, the combination of cetylalcohol and stearyl alcohol is synergistic and results in excellentquality foams as shown in formulation 46 which contains cetostearylalcohol, a mixture of 50% cetyl alcohol and 50% stearyl alcohol. Suchexcellent quality foam was not observed in the examples containingeither cetyl alcohol alone or stearyl alcohol alone. Thus, we havediscovered that a combination of two fatty alcohols having a carbonschain length of 16 to 18 has a synergistic effect and substantiallyenhances the foaming properties of hydro-alcoholic formulations.

TABLE 3 Formulations containing fatty alcohols and fatty acids ofdifferent carbon chain length Formulation 40 41 42 43 44 45 46Ingredient % w/w % w/w % w/w % w/w % w/w % w/w % w/w Ethanol 50.00 50.0050.00 50.00 50.00 50.00 50.00 Water 47.00 47.00 47.00 47.00 47.00 47.0047.00 Stearic acid (C18) 3.00 — — — — — — Isostearic acid (C18) — 3.00 —— — — — Myristyl alcohol — — 3.00 — — — — (C14) Cetyl alcohol (C16) — —— 3.00 — — — Stearyl alcohol (C18) — — — — 3.00 — — Behenyl alcohol — —— — — 3.00 — (C22) Cetostearyl alcohol — — — — — — 3.00 (C16 + C18)Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Propellant AP-708.00 8.00 8.00 8.00 8.00 8.00 8.00 Results Foam Quality Good Poor PoorFairly Good Fair Excellent Good

Example 4 Thermal Stability—Comparative Example

A foam formulation (Formulation 46B) was compared with a foamformulation from patent U.S. Pat. No. 6,126,920, Example 1, as describedin Table 4. Both foam samples were placed on fingers of a male volunteerand the thermal stability of each of the foams was assessed by measuringthe time it takes to melt on the fingers. The foam formulation 46B wasthermally stable and did not melt on contact with the skin for more thanthree minutes, thus providing an easy and convenient application for theuser of the product. In contrast, the foam formulation from U.S. Pat.No. 6,126,920, Example 1, which is described as a “quick-breaking” foam,was thermally unstable and quickly liquefied and melted on contact withthe skin within 15 seconds, making the product application difficult forthe user and causing the drug to absorb on the fingers, rather than onthe intended target site of treatment.

TABLE 4 Comparative example Formulation Sample according to U.S. Pat.No. 46B 6,126,920 Example 1 % w/w % w/w Ingredient Ethanol 50.00 57.79Purified water 47.00 33.69 Propylene glycol — 2.00 Cetostearyl alcohol3.00 — Citric acid — 0.073 Potassium citrate — 0.027 Polysorbate 60 —0.40 Octadecan-1-ol (stearyl alcohol) — 0.50 Cetyl alcohol — 1.10Betamethasone valerate 0.12 0.12 Total 100 Hydrocarbon propellant 8.004.30 (butane/propane/isobutane) Total 100 Results Time to 50% melting >3minutes 15 seconds

Example 5 Hydro-Alcoholic Formulations Examining the Effect of ReplacingCetostearyl Alcohol with Polymer

Parameters such as foam quality, collapse time and product clarity wereevaluated, and results described in Table 5 below. The presence of afatty alcohol (or similarly a fatty acid) seems compulsory, given thatthe formulation lacking cetostearyl alcohol did not give foam but abubbly liquid.

TABLE 5 Formulations with and without cetostearyl alcohol Formulation 2930 % w/w % w/w Ingredient Ethanol 50.20 50.20 Purified water 43.20 43.00Propylene glycol 5.00 5.00 Hydroxypropyl cellulose 1.50 — Cetostearylalcohol — 1.70 Citric acid 0.07 0.07 Sodium citrate 0.03 0.03 Total100.00 100.00 Propellant AP-70 8.00 8.00 Results Foam Quality PoorExcellent Collapse Time at 36° C. (sec) — >180 Product clarity Yes Yes

Example 6 Hydro-Alcoholic Formulations Containing DifferentConcentrations of Fatty Alcohol

Parameters such as foam quality, collapse time and foam density wereevaluated in foam formulations containing various concentrations offatty alcohol, and the results are described in Table 6 below. Breakablefoams of excellent quality were obtained in hydro-alcoholic formulationscontaining from 1% to 10% Cetostearyl alcohol. Interestingly, it appearsthat foams containing high amounts of cetostearyl alcohol have a lowerdensity than foams containing lower amounts of cetostearyl alcohol. Inone or more embodiments there is provided a low density foam. In someembodiments the density is about 0.1 g/mL or less. In some embodimentsthe density is about 0.08 g/mL or less. In some embodiments the densityis about 0.07 g/mL or less. In some embodiments the density is about0.06 g/mL.

TABLE 6 Formulations containing different concentrations of fattyalcohol Formulation 55 56 57 58 59 60 61 Ingredient % w/w % w/w % w/w %w/w % w/w % w/w % w/w Ethanol 50.0 50.0 50.0 50.0 50.0 50.0 50.0Purified water 40.0 40.0 40.0 40.0 40.0 40.0 40.0 Propylene 9.0 8.0 7.06.0 5.0 2.5 — glycol Cetostearyl 1.0 2.0 3.0 4.0 5.0 7.5 10.0 alcoholTotal 100.00 100.00 100.00 100.00 100.00 100.00 100.00 AP-70 8.00 8.008.00 8.00 8.00 8.00 8.00 Results Foam Quality Excellent ExcellentExcellent Excellent Excellent Excellent Excellent CollapseTime >180 >180 >180 >180 >180 >180 >180 Foam Density 0.114 0.073 0.0840.060 0.065 0.060 0.060

Example 7 Hydro-Alcoholic Formulations Containing Different PropellantTypes and Amounts

Parameters such as foam quality, collapse time and foam density wereevaluated in foam formulations containing different propellant types andamounts as described in Table 7a below. Breakable foams of excellentquality were obtained in hydro-alcoholic formulations containing A-46,Dymel 134a and various amounts of AP-70. Interestingly, it appears thatfoams containing hydrocarbon propellants have a low density as well asfoams containing low amounts of propellant. Surprisingly, it wasobserved that as the amount of propellant increased form 6% to 8% to 12%to 14% the density also increased in small amounts. Further, examinationof the results of Example 7b show that this phenomena continues as thepropellant is increased to 20% and 30%. So by varying the amount ofpropellant and type the density of resultant foam can be modified. Insome embodiments the density is about 0.2 g/mL or less. In someembodiments the density is about 0.16 g/mL or less. In some embodimentsthe density is about 0.12 g/mL or less. In some embodiments the densityis about 0.11 g/mL or less.

TABLE 7a Formulations containing different concentrations of fattyalcohol Formulation 62 63 64 65 66 67 Ingredient % w/w % w/w % w/w % w/w% w/w % w/w Ethanol 50.0 50.0 50.0 50.0 50.0 50.0 Purified water 40.040.0 40.0 40.0 40.0 40.0 Propylene glycol 7.0 7.0 7.0 7.0 7.0 7.0Cetostearyl 3.0 3.0 3.0 3.0 3.0 3.0 alcohol Total 100.00 100.00 100.00100.00 100.00 100.00 AP-70 6.00 10.00 12.00 14.00 — — A-46 — — — — 8.00— Dymel 134a — — — — — 8.00 Results Foam Quality Excellent ExcellentExcellent Excellent Excellent Excellent CollapseTime >180 >180 >180 >180 >180 >180 Foam Density 0.068 0.073 0.082 0.0900.063 0.093

As can be seen from the experiment below there is a limit as to how muchpropellant can be added. Breakable foams of good quality were obtainedin hydro-alcoholic formulations containing AP-70 at a concentration upto about 30%. These foams were thermally stable at 36° C. for more than3 minutes yet breakable upon shear force. However, with propellantamounts of about 37%, only poor quality foams were produced. Withoutbeing bound by any theory this may in part be connected to thehydro-alcoholic nature of the formulations and high ethanol level.

TABLE 7b Formulations containing different concentrations of propellantFormulation 68 69 70 % w/w % w/w % w/w Ingredient Ethanol 50.0 50.0 50.0Purified water 40.0 40.0 40.0 Propylene glycol 7.0 7.0 7.0 Cetostearylalcohol 3.0 3.0 3.0 Total 100.00 100.00 100.00 AP-70 20.00 30.00 37.00Results Foam Quality Good Good Poor Collapse Time >180 >180 — FoamDensity 0.121 0.158 —

Example 8 Hydro-Alcoholic Formulations Containing Different Ratios ofFatty Alcohol

Parameters such as foam quality, collapse time and foam density wereevaluated in foam formulations containing different ratios of cetylalcohol and stearyl alcohol as described in Table 8 below.

TABLE 8 Formulations containing different ratios of fatty alcoholFormulation 71 72 73 74 75 % w/w % w/w % w/w % w/w % w/w IngredientEthanol 58.0 58.0 58.0 58.0 58.0 Purified water 32.0 32.0 32.0 32.0 32.0Propylene glycol 8.4 8.4 8.4 8.4 8.4 Cetyl alcohol 1.5 1.1 0.8 0.5 0.1Stearyl alcohol 0.1 0.5 0.8 1.1 1.5 Total 100.00 100.00 100.00 100.00100.00 AP-70 8.00 8.00 8.00 8.00 8.00 Results Foam Quality Poor FairGood Fairly Good Fair Collapse Time — — >180 Rapid — Foam Density — —0.144 — — Cetyl:stearyl 15:1 2.2:1 1:1 1:2.2 1:15 alcohol ratio(i.e.11:5) (i.e.5:11)

Surprisingly, it appears that the foam quality can be strongly influenceby the ratio of mixtures of fatty alcohols such as cetyl and stearylalcohol. Formulations having a cetyl:stearyl alcohol ratio of about 1gave breakable quality foam being stable for more than 3 minutes at 36°C. However, when the ratio of cetyl:stearyl alcohol was about 11:5 orhigher, or was about 1:15 or lower, no quality foam could be produced.It was further noted that stearyl alcohol appears to have a moresignificant role in the synergistic relationship than cetyl alcohol. Incontrast, it appears that Example 1 of U.S. Pat. No. 6,126,920 relies onthe surfactant present in the composition to produce quick-breakingfoams. In short the prior art did not contemplate surfactant-free andpolymer-free hydro-alcoholic that can produce thermally stable breakablefoams.

Example 9 Hydro-Alcoholic Formulations Containing Fatty Alcohol andFatty Acids

Parameters such as foam quality, collapse time and foam density wereevaluated in foam formulations containing mixtures of fatty alcohol andfatty acids as described in Table 9 below.

TABLE 9a Formulations mixtures of fatty alcohol and fatty acidsFormulation 76 77 % w/w % w/w Ingredient Ethanol 58.0 58.0 Purifiedwater 32.0 32.0 Propylene glycol 8.4 8.4 Cetyl alcohol 0.8 — Myristylalcohol 0.8 — Stearyl alcohol — 0.8 Stearic acid — 0.8 Total 100.00100.00 AP-70 8.00 8.00 Results Foam Quality Excellent Excellent CollapseTime at 36° C. (sec) 85 >180 Foam Density (g/mL) 0.093 0.074

When cetyl alcohol and myristyl alcohol are used alone inhydro-alcoholic formulations, poor and fairly good foams are obtainedrespectively, as shown in formulations 42 and 43 described in Example 3.Poor foam collapses rapidly. Surprisingly however, when 0.8% myristylalcohol is combined with 0.8% cetyl alcohol, a short term stablebreakable foam of excellent quality is achieved having a low density anda collapse time well in excess of a minute. So the combination of cetylalcohol and myristyl alcohol achieves a synergistic effect. When stearylalcohol and stearic acid are used alone in hydro-alcoholic formulations,good quality foams are obtained, as shown in formulations 40 and 44described in previous example 3. Surprisingly however, a breakable foamof excellent quality having a low density and with a collapse time inexcess of 180 sec at 36° C. was obtained with a combination of 0.8%stearic acid with 0.8% stearyl alcohol.

In one or more embodiments, there is provided a hydro-alcoholic foamableformulation which provides a short term stable breakable foam with acollapse time of 60 sec or more at 36° C., and containing a combinationof two or more fatty alcohols. In one or more embodiments thecombination is synergistic.

In one or more embodiments, there is provided a hydro-alcoholic foamableformulation which provides a short term stable breakable foam with acollapse time of 180 seconds or more at 36° C., and containing acombination of one or more fatty alcohols with one or more fatty acids.

Example 10 Hydro-Alcoholic Formulations Containing Different Ratios ofFatty Acid

Parameters such as foam quality, collapse time and foam density wereevaluated in foam formulations containing different ratios of myristicacid and stearic acid as described in Table 10 below.

TABLE 10 Formulations containing different ratios of fatty acidFormulation 79 80 81 % w/w % w/w % w/w Ingredient Ethanol 58.0 58.0 58.0Purified water 32.0 32.0 32.0 Propylene glycol 8.4 8.4 8.4 Myristic acid1.1 0.8 0.5 Stearic acid 0.5 0.8 1.1 Total 100.00 100.00 100.00 AP-708.00 8.00 8.00 Results Foam Quality Poor Fairly Good GoodMyristic:stearic acid ratio 2.2:1 (i.e.11:5) 1:1 1:2.2 (i.e.5:11)

Surprisingly, it appears that the foam quality can be influenced by theratio of mixtures of fatty acids, such as myristic and stearic acid.Formulations having a myristic:stearic acid ratio between about 5:11gave foams of good quality. However, when the ratio of myristic:stearicacid was about 11:5 only poor quality could be produced. In one or moreembodiments, the ratio of fatty acids can be optimized in order toobtain foams of good or excellent quality. In one or more embodimentsthe combination of two or more fatty acids can enable lower amounts tobe used. So whilst stearic acid alone can produce good quality foam athigher concentrations (see Example 3) as can be seen herein loweramounts were used in combination with myristic acid

Example 11 Hydro-Alcoholic Formulations Containing Isopropanol

A foam formulation was prepared containing isopropanol (C₃H₇OH), whichis another example of short chain alcohol. Parameters such as foamquality and collapse time were evaluated. As described in Table 11, afoam of good quality that did not collapse after 180 seconds wasobtained in a formulation containing isopropanol.

TABLE 11 Formulation containing isopropanol Formulation 82 % w/wIngredient Isopropyl alcohol 40.00 Hexylene Glycol 12.00 Purified Water31.00 Propylene Glycol 13.00 Stearyl alcohol 4.00 Total 100.00Propellant AP70 8.00 Results Foam Quality Good Foam Density (g/mL) 0.223Collapse Time at 36° C. (sec) >180

So, it follows that the above revelations as to how to achieve a shortterm stable breakable foam that is a foam which is stable upon exposureto body temperature despite the presence of a high level of ethanolshould apply likewise mutatis mutandis to other short chain alcohols,such as, isopropanol, propanol, butanaol, iso-butanol, t-butanol andpentanol. In one or more embodiments there is provided a short termstable breakable foam formulation comprising one or more short chainalcohols.

1. A foamable composition comprising: a) a short chain alcohol; b)water; c) a foaming booster comprising at least one fatty alcohol or atleast one fatty acid or a combination thereof; and d) a liquefied orcompressed gas propellant at a concentration of about 3% to about 30% byweight of the total composition; wherein the foamable composition issurfactant free; wherein the foamable composition is substantiallypolymeric agent free; wherein the percent by weight is based on weightfoamable composition; wherein the ratio range of composition other thanpropellant to propellant is from about 100:3 to about 100:30; andwherein upon dispensing the foamable carrier composition forms a foam ofquality that is thermally stable at a temperature of 36° C. having acollapse time about or more than 60 seconds.
 2. The composition of claim1, wherein the short chain alcohol is selected from the group consistingof ethanol or isopropanol.
 3. The composition of claim 1, wherein thefoaming booster combination is a synergistic combination that canimprove the foam quality and or thermal stability of the composition. 4.The composition of claim 1, further comprising at least one activeagent.
 5. The composition of claim 4, wherein the active agent isselected form the group consisting of an active herbal extract, anacaricides, an age spot and keratose removing agent, an allergen, analpha hydroxyl acid, an analgesic agent, an anesthetic, an immunogenicsubstance, an antiacne agent, an antiallergic agent, an antiaging agent,an antibacterial agent, an antibiotic, an antiburn agent, an anticanceragent, an antidandruff agent, an antidepressant, an antidermatitisagent, an antiedemic anent, an antifungal agent, an antihistamine, anantihelminth agent, an antihyperkeratolyte agent, an anti-infectiveagent, an anti-inflammatory agent, aft antiirritant, an antilipemicagent, an antimicrobial agent, an antimycotic agent, an antioxidant, anantiparasitic agent, an anti-pigmentation agent, an antiproliferativeagent, an antipruritic agent, an antipsoriatic agent, an antirosaceaagent, an antiseborrheic agent, an antiseptic agent, an antiswellingagent, an antiviral agent, an anti-wart agent, an anti-wrinkle agent, anantiyeast agents, an astringent, a beta-hydroxy acid, benzoyl peroxide,benzoyl chloride a, topical cardiovascular agent, a chemotherapeuticagent, a corticosteroid, an immunogenic substance, a dicarboxylic acid,a disinfectant, a fungicide, a hair growth regulator, a haptene, ahormone, a hydroxy acid, an immunosuppressant, an immunoregulatingagent, an immunomodulator, an insecticide, an insect repellent, akeratolytic agent, a lactam, a local anesthetic agent, a lubricatingagent, a masking agent, a metals, a metal oxide, a mitocide, aneuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a protein, a photodynamic therapyagent, a radical scavenger, a refatting agent, a retinoid, a sanative, ascabicide, a self tanning agent, silicone talc, a skin protective agent,a skin whitening agent, a steroid, a steroid hormone, a steroidalanti-inflammatory agent, a vasoconstrictor, a vasodilator, a vitamin, avitamin A, a vitamin A derivative, a vitamin B, a vitamin B derivative,a vitamin C, a vitamin C derivative, a vitamin D, a vitamin Dderivative, a vitamin D analog, a vitamin F, a vitamin F derivative, avitamin K, a vitamin K derivative, a wound healing agent and a wartremover and mixtures thereof.
 6. The composition of claim 1, wherein thecomposition is transparent upon pressurization by the gas propellant. 7.The composition of claim 1, wherein the composition further includesabout 0.1% to about 5% of a humectant.
 8. The composition of claim 7,wherein the humectant is selected from the group consisting of PEG 400,propylene glycol and glycerin.
 9. The composition of claim 1, whereinthe composition is essentially polymer free.
 10. The composition ofclaim 1, wherein the fatty acid or fatty alcohol is selected from thegroup consisting of (i) 14 to 18 carbon atoms in its carbon chain or(ii) 16 to 18 carbon atoms in its carbon chain.
 11. The composition ofclaim 3, wherein the synergistic combination is of at least two fattyalcohols.
 12. The composition of claim 11, wherein the combination offatty alcohols is selected form a group comprising (i) a stearyl alcoholand cetyl alcohol or (ii) cetyl alcohol and myristyl alcohol.
 13. Thecomposition of claim 1, wherein the foaming booster is between about 1%and about 10% by weight of the composition.
 14. The composition of claim11, wherein the ratio between at least two fatty alcohols is betweenabout 11:5 and about 5:11.
 15. The composition of claim 11, wherein theratio between at least two fatty alcohols is about 1:1.
 16. Thecomposition of claim 1, wherein the short chain alcohol is selected fromthe group consisting of (i) at least about 15% by weight of thecomposition or (ii) is between about 20% and 60% by weight of thecomposition or (iii) is between about 30% and 60% by weight of thecomposition or (iv) is between about 40% and 60% by weight of thecomposition.
 17. The composition of claim 1, which is thermally stableat 36 ° C. having a collapse time of about or more than 120 seconds. 18.The composition of claim 1, which is thermally stable at 36 ° C. havinga collapse time of about or more than 180 seconds.
 19. The compositionof claim 1, further comprising a hydrophilic solvent.
 20. Thecomposition of claim 1, wherein the short chain alcohol is replaced by ahydrophilic solvent.
 21. The composition of claim 1, wherein the foam isa breakable foam that is thermally stable upon dispensing yet breakseasily upon application of shear force.
 22. The foamable composition ofclaim 1, wherein the foamable composition comprises 0% to 0.1% polymericagent.
 23. A foamable composition comprising: a) a short chain alcohol;b) water; c) a foaming booster comprising at least one fatty alcohol orat least one fatty acid or a combination thereof or a synergisticcombination of two or more fatty alcohols; and d) a liquefied orcompressed gas propellant at a concentration of about 3% to about 30% byweight of the total composition; wherein the foamable composition issurfactant free; wherein the foamable composition is substantiallypolymeric agent free; wherein the percent by weight is based on weightfoamable composition; wherein the ratio range of composition other thanpropellant to propellant is from about 100:3 to about 100:30; andwherein the ratio between the two fatty alcohols is between about 11:5and about 5:11.
 24. The foamable composition of claim 23, wherein theratio between the two fatty alcohols is about 1:1.
 25. The foamablecomposition of claim 23, further comprising an active agent.
 26. Thefoamable composition of claim 23, wherein the foamable compositioncomprises 0% to 0.1% polymeric agent
 27. A method of preventing orameliorating or eliminating or treating or alleviating a dermatologicalor a mucosal disorder, the method comprising: applying a foamablecomposition to a surface having the dermatological or mucosal disorderin need of treatment, said foamable composition comprising: a) a shortchain alcohol; b) water; c) a foaming booster comprising at least onefatty alcohol or at least one fatty acid or combination thereof or asynergistic combination of two or more fatty alcohols; and d) aliquefied or compressed gas propellant at a concentration of about 3% toabout 30% by weight of the total composition; wherein the foamablecomposition is surfactant free; wherein the foamable composition issubstantially polymeric agent free; wherein the percent by weight isbased on weight foamable composition; wherein the ratio of compositionother than propellant to propellant is from about 100:3 to about 100:30;and wherein upon dispensing the foamable carrier composition forms afoam that is thermally stable at a temperature of 36° C. having acollapse time of about or more than 60 seconds.
 28. The method of claim27, wherein the foamable composition further comprises at least oneactive agent.
 29. The method of claim 27, wherein the foamablecomposition comprises 0% to 0.1% polymeric agent.
 30. A method ofpreventing or ameliorating or eliminating or treating or alleviating adermatological or a mucosal disorder, the method comprising: applying afoamable composition to a surface having the dermatological or mucosaldisorder in need of treatment, said foamable composition comprising: a)a short chain alcohol; b) water c) a foaming booster comprising at leastone fatty alcohol or at least one fatty acid or a combination thereof;and d) a liquefied or compressed gas propellant at a concentration ofabout 3% to about 30% by weight of the total composition; wherein thefoamable composition is surfactant free; wherein the foamablecomposition is substantially polymeric agent free; wherein the percentby weight is based on weight foamable composition; wherein the ratiorange of composition other than propellant to propellant is from about100:3 to about 100:30; and wherein upon dispensing the foamablecomposition forms a foam of quality that is thermally stable at atemperature of 36° C. having a collapse time about or more than 60seconds.
 31. The method of claim 30, wherein the foamable compositionfurther comprises at least one active agent.
 32. The method of claim 30,wherein the foamable composition comprises 0% to 0.1% polymeric agent.